Journal articles
Dennis J, Jones A, Shields B, Hattersley A (In Press). Comparison of causal forest and regression-based approaches to evaluate treatment effect heterogeneity: an application for type 2 diabetes precision medicine.
BMC Medical Informatics and Decision MakingAbstract:
Comparison of causal forest and regression-based approaches to evaluate treatment effect heterogeneity: an application for type 2 diabetes precision medicine
Objective: Precision medicine requires reliable identification of variation in patient-level outcomes with different available treatments, often termed treatment effect heterogeneity. We aimed to evaluate the comparative utility of individualized treatment selection strategies based on predicted individual-level treatment effects from a causal forest machine learning algorithm and a penalized regression model.
Methods: Cohort study characterizing individual-level glucose-lowering response (6 month reduction in HbA1c) in people with type 2 diabetes initiating SGLT2-inhibitor or DPP4-inhibitor therapy. Model development set comprised 1,428 participants in the CANTATA-D and CANTATA-D2 randomised clinical trials of SGLT2-inhibitors versus DPP4-inhibitors. For external validation, calibration of observed versus predicted differences in HbA1c in patient strata defined by size of predicted HbA1c benefit was evaluated in 18,741 patients in UK primary care (Clinical Practice Research Datalink).
Results: Heterogeneity in treatment effects was detected in clinical trial participants with both approaches (proportion predicted to have a benefit on SGLT2-inhibitor therapy over DPP4-inhibitor therapy: causal forest: 98.6%; penalized regression: 81.7%). In validation, calibration was good with penalized regression but sub-optimal with causal forest. A strata with an HbA1c benefit >10 mmol/mol with SGLT2-inhibitors (3.7% of patients, observed benefit 11.0 mmol/mol [95%CI 8.0-14.0]) was identified using penalized regression but not causal forest, and a much larger strata with an HbA1c benefit 5-10 mmol with SGLT2-inhibitors was identified with penalized regression (regression: 20.9% of patients, observed benefit 7.8 mmol/mol (95%CI 6.7-8.9); causal forest 11.6%, observed benefit 8.7 mmol/mol (95%CI 7.4-10.1).
Conclusions: Consistent with recent results for outcome prediction with clinical data, when evaluating treatment effect heterogeneity researchers should not rely on causal forest or other similar machine learning algorithms alone, and must compare outputs with standard regression, which in this evaluation was superior.
Abstract.
Dennis JM, Young KG, McGovern AP, Mateen BA, Vollmer SJ, Simpson MD, Henley WE, Holman RR, Sattar N, Pearson ER, et al (In Press). Derivation and validation of a type 2 diabetes treatment selection algorithm for SGLT2-inhibitor and DPP4-inhibitor therapies based on glucose-lowering efficacy: cohort study using trial and routine clinical data.
Abstract:
Derivation and validation of a type 2 diabetes treatment selection algorithm for SGLT2-inhibitor and DPP4-inhibitor therapies based on glucose-lowering efficacy: cohort study using trial and routine clinical data
AbstractObjectiveTo establish whether clinical patient characteristics routinely measured in primary care can identify people with differing short-term benefits and risks for SGLT2-inhibitor and DPP4-inhibitor therapies, and to derive and validate a treatment selection algorithm to identify the likely optimal therapy for individual patients.DesignProspective cohort study.SettingRoutine clinical data from United Kingdom general practice (Clinical Practice Research Datalink [CPRD]), and individual-level clinical trial data from 14 multi-country trials of SGLT2-inhibitor and DPP4-inhibitor therapies.Participants26,877 new users of SGLT2-inhibitor and DPP4-inhibitor therapy in CPRD over 2013-2019, and 10,414 participants randomised to SGLT2-inhibitor or DPP4-inhibitor therapy in 14 clinical trials, including 3 head-to-head trials of the two therapies (n=2,499).Main outcome measuresThe primary outcome was achieved HbA1c 6 months after initiating therapy. Clinical features associated with differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies were identified in routine clinical data, with associations then tested in trial data. A multivariable treatment selection algorithm to predict differential HbA1c outcomes was developed in a CPRD derivation cohort (n=14,069), with validation in a CPRD validation cohort (n=9,376) and the head-to-head trials. In CPRD, we further explored the relationship between model predictions and secondary outcomes of weight loss and treatment discontinuation.ResultsThe final treatment selection algorithm included HbA1c, eGFR, ALT, age, and BMI, which were identified as predictors of differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies using both routine and trial data. In validation cohorts, patient strata predicted to have a ≥5 mmol/mol HbA1c reduction with SGLT2-inhibitor therapy compared with DPP4-inhibitor therapy (38.8% of CPRD validation sample) had an observed greater reduction of 8.8 mmol/mol [95%CI 7.8-9.8] in the CPRD validation sample, a 5.8 mmol/mol (95%CI 3.9-7.7) greater reduction in the Cantata D/D2 trials, and a 6.6 mmol/mol [95%CI 2.2-11.0]) greater reduction in the BI1245.20 trial. In CPRD, there was a greater weight reduction with SGLT2-inhibitor therapy regardless of predicted glycaemic benefit. Strata predicted to have greater reduction in HbA1c on SGLT2-inhibitor therapy had a similar risk of discontinuation as on DPP4-inhibitor therapy. In contrast, strata predicted to have greater reduction in HbA1c with DPP4-inhibitor therapy were half as likely to discontinue DPP4-inhibitor therapy than SGLT2-inhibitor therapy.ConclusionsRoutinely measured clinical features are robustly associated with differential glycaemic responses to SGLT2-inhibitor and DPP4-inhibitor therapies. Combining features into a treatment selection algorithm can inform clinical decisions concerning optimal type 2 diabetes treatment choices.Key messagesWhat is already known on this subjectDespite there being multiple glucose-lowering treatment options available for people with type 2 diabetes, current guidelines do not provide clear advice on selecting the optimal treatment for most patients.It is unknown whether routinely measured clinical features modify the risks and benefits of two common treatment options, DPP4-inhibitor or SGLT2-inhibitor therapy, and which could be used to target these treatments to those patients most likely to benefit.What this study addsUsing data from 10,414 participants in 14 randomised trials, and 26,877 patients in UK primary care, we show several routinely available clinical features, notably glycated haemoglobin (HbA1c) and kidney function, are robustly associated with differential HbA1c responses to initiating SGLT2-inhibitor and DPP4-inhibitor therapies.Combining clinical features into a multivariable treatment selection model identifies validated patient strata with 1) a >5 mmol/mol HbA1c benefit for SGLT2-i therapy compared with DPP4-inhibitor therapy ; 2) a 50% reduced risk of early treatment discontinuation with DPP4-inhibitor therapy compared with SGLT2-inhibitor therapy.Our findings demonstrate a precision medicine approach based on routine clinical features can inform clinical decisions concerning optimal type 2 diabetes treatment choices.
Abstract.
Lynam A, McDonald T, Hill A, Dennis J, Oram R, Pearson E, Weedon M, Hattersley A, Owen K, Shields B, et al (In Press). Development and validation of multivariable clinical diagnostic models to identify type 1 diabetes requiring rapid insulin therapy in adults aged 18 to 50. BMJ Open
Clissold R, Fulford J, Hudson M, Shields B, McDonald T, Ellard S, Hattersley A, Bingham C (In Press). Exocrine pancreatic dysfunction is common in HNF1B-associated renal disease and can be symptomatic. Clinical Kidney Journal
Young KG, McDonald TJ, Shields BM (In Press). Glycated haemoglobin measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care.
Abstract:
Glycated haemoglobin measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care
AbstractData linkage of cohort or RCT data with routinely collected data is becoming increasingly commonplace, and this often involves combining biomarker measurements from different sources. However, sources may have different biases due to differences in assay method and calibration. Combining these measurements, or diagnoses based on these measurements, is therefore not always valid. We highlight an example using glycated haemoglobin A1c (HbA1c) test results from two different sources in UK Biobank data.
Abstract.
Shields B, Hattersley A, Farmer A (In Press). Identifying routine clinical predictors of non-adherence to second line therapies in Type 2 diabetes: a retrospective cohort analysis in a large primary care database. Diabetes, Obesity and Metabolism
Peters J, Anderson R, Shields B, Hudson M, Shepherd M, McDonald T, Hattersley A, Hyde C (In Press). Strategies to Identify Individuals with Monogenic Diabetes: Results of an Economic Evaluation. BMJ Open
Leete P, Oram R, McDonald T, Ziller C, Hattersley A, Richardson S, Morgan N (In Press). Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis. Diabetologia
Thomas NJ, Hill AV, Dayan CM, Oram RA, McDonald TJ, Shields BM, Jones AG, Simon G, Ramos A, Norris A, et al (2023). Age of Diagnosis Does Not Alter the Presentation or Progression of Robustly Defined Adult-Onset Type 1 Diabetes.
Diabetes Care,
46(6), 1156-1163.
Abstract:
Age of Diagnosis Does Not Alter the Presentation or Progression of Robustly Defined Adult-Onset Type 1 Diabetes
. OBJECTIVE
. To determine whether presentation, progression, and genetic susceptibility of robustly defined adult-onset type 1 diabetes (T1D) are altered by diagnosis age.
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. RESEARCH DESIGN AND METHODS
. We compared the relationship between diagnosis age and presentation, C-peptide loss (annual change in urine C-peptide–creatinine ratio [UCPCR]), and genetic susceptibility (T1D genetic risk score [GRS]) in adults with confirmed T1D in the prospective StartRight study, 1,798 adults with new-onset diabetes. T1D was defined in two ways: two or more positive islet autoantibodies (of GAD antibody, IA-2 antigen, and ZnT8 autoantibody) irrespective of clinical diagnosis (n = 385) or one positive islet autoantibody and a clinical diagnosis of T1D (n = 180).
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. RESULTS
. In continuous analysis, age of diagnosis was not associated with C-peptide loss for either definition of T1D (P > 0.1), with mean (95% CI) annual C-peptide loss in those diagnosed before and after 35 years of age (median age of T1D defined by two or more positive autoantibodies): 39% (31–46) vs. 44% (38–50) with two or more positive islet autoantibodies and 43% (33–51) vs. 39% (31–46) with clinician diagnosis confirmed by one positive islet autoantibody (P > 0.1). Baseline C-peptide and T1D GRS were unaffected by age of diagnosis or T1D definition (P > 0.1). In T1D defined by two or more autoantibodies, presentation severity was similar in those diagnosed before and after 35 years of age: unintentional weight loss, 80% (95% CI 74–85) vs. 82% (76–87); ketoacidosis, 24% (18–30) vs. 19% (14–25); and presentation glucose, 21 mmol/L (19–22) vs. 21 mmol/L (20–22) (all P ≥ 0.1). Despite similar presentation, older adults were less likely to be diagnosed with T1D, insulin-treated, or admitted to hospital.
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. CONCLUSIONS
. When adult-onset T1D is robustly defined, the presentation characteristics, progression, and T1D genetic susceptibility are not altered by age of diagnosis.
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Abstract.
Solé-Navais P, Flatley C, Steinthorsdottir V, Vaudel M, Juodakis J, Chen J, Laisk T, LaBella AL, Westergaard D, Bacelis J, et al (2023). Author Correction: Genetic effects on the timing of parturition and links to fetal birth weight.
Nat Genet,
55(7).
Author URL.
Young KG, McGovern AP, Barroso I, Hattersley AT, Jones AG, Shields BM, Thomas NJ, Dennis JM (2023). Correction to: the impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis.
Diabetologia,
66(8).
Author URL.
Solé-Navais P, Flatley C, Steinthorsdottir V, Vaudel M, Juodakis J, Chen J, Laisk T, LaBella AL, Westergaard D, Bacelis J, et al (2023). Genetic effects on the timing of parturition and links to fetal birth weight.
Nat Genet,
55(4), 559-567.
Abstract:
Genetic effects on the timing of parturition and links to fetal birth weight.
The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
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Author URL.
Young KG, McGovern AP, Barroso I, Hattersley AT, Jones AG, Shields BM, Thomas NJ, Dennis JM (2023). HbA1c screening for the diagnosis of diabetes. Reply to Brož J, Brabec M, Krollová P et al [letter].
Diabetologia,
66(8), 1578-1579.
Author URL.
Decina CS, Hopkins R, Bowden J, Shields BM, Lawlor DA, Warrington NM, Evans DM, Freathy RM, Beaumont RN (2023). Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study.
Int J Epidemiol,
52(1), 178-189.
Abstract:
Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study.
BACKGROUND: Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. METHODS: We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768). RESULTS: Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: -50, 6); P = 0.13] and UKB [-28 g (95% CI: -31, -25); P = 1.8 × 10-75]. The MR causal effect estimate was directionally consistent, but smaller [-11 g (95% CI: -25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10-22], consistent with that previously published in women and men. CONCLUSION: the marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.
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Author URL.
Nakanga WP, Balungi P, Niwaha AJ, Shields BM, Hughes P, Andrews RC, Mc Donald TJ, Nyirenda MJ, Hattersley AT (2022). Alternative pre-analytic sample handling techniques for glucose measurement in the absence of fluoride tubes in low resource settings.
PLoS One,
17(2).
Abstract:
Alternative pre-analytic sample handling techniques for glucose measurement in the absence of fluoride tubes in low resource settings.
INTRODUCTION: Sodium fluoride (NaF) tubes are the recommended tubes for glucose measurements, but these are expensive, have limited number of uses, and are not always available in low resource settings. Alternative sample handling techniques are thus needed. We compared glucose stability in samples collected in various tubes exposed to different pre-analytical conditions in Uganda. METHODS: Random (non-fasted) blood samples were drawn from nine healthy participants into NaF, Ethylenediaminetetraacetic acid (EDTA), and plain serum tubes. The samples were kept un-centrifuged or centrifuged with plasma or serum pipetted into aliquots, placed in cool box with ice or at room temperature and were stored in a permanent freezer after 0, 2, 6, 12 and 24 hours post blood draw before glucose analysis. RESULTS: Rapid decline in glucose concentrations was observed when compared to baseline in serum (declined to 64%) and EDTA-plasma (declined to 77%) after 6 hours when samples were un-centrifuged at room temperature whilst NaF-plasma was stable after 24 hours in the same condition. Un-centrifuged EDTA-plasma kept on ice was stable for up to 6 hours but serum was not stable (degraded to 92%) in the same conditions. Early centrifugation prevented glucose decline even at room temperature regardless of the primary tube used with serum, EDTA-plasma and NaF-plasma after 24 hours. CONCLUSION: in low resource settings we recommend use of EDTA tubes placed in cool box with ice and analysed within 6 hours as an alternative to NaF tubes. Alternatively, immediate separation of blood with manual hand centrifuges will allow any tube to be used even in remote settings with no electricity.
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Author URL.
Haulder M, Hughes AE, Beaumont RN, Knight BA, Hattersley AT, Shields BM, Freathy RM (2022). Assessing whether genetic scores explain extra variation in birthweight, when added to clinical and anthropometric measures.
BMC Pediatrics,
22(1).
Abstract:
Assessing whether genetic scores explain extra variation in birthweight, when added to clinical and anthropometric measures
Abstract
. Background
. Human birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables.
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. Methods
. We analysed 549 European-ancestry parent-offspring trios from a UK community-based birth cohort.
. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics, and parental anthropometric variables. We used R-Squared (R2) to estimate variance explained, adjusted R-squared (Adj-R2) to assess improvement in model fit from added predictors, and F-tests to compare nested models.
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. Results
. Maternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R2 = 0.233 vs Adj-R2 = 0.210, p < 0.001). Fetal genetic score improved variance explained (Adj-R2 = 0.264 vs 0.248, p < 0.001) when added to maternal characteristics and parental heights.
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. Conclusions
. Genetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.
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Abstract.
Locke JM, Dusatkova P, Colclough K, Hughes AE, Dennis JM, Shields B, Flanagan SE, Shepherd MH, Dempster EL, Hattersley AT, et al (2022). Association of birthweight and penetrance of diabetes in individuals with HNF4A-MODY: a cohort study.
Diabetologia,
65(1), 246-249.
Author URL.
Niwaha AJ, Rodgers LR, Carr ALJ, Balungi PA, Mwebaze R, Hattersley AT, Shields BM, Nyirenda MJ, Jones AG (2022). Continuous glucose monitoring demonstrates low risk of clinically significant hypoglycemia associated with sulphonylurea treatment in an African type 2 diabetes population: results from the OPTIMAL observational multicenter study.
BMJ Open Diabetes Res Care,
10(2).
Abstract:
Continuous glucose monitoring demonstrates low risk of clinically significant hypoglycemia associated with sulphonylurea treatment in an African type 2 diabetes population: results from the OPTIMAL observational multicenter study.
INTRODUCTION: People living with diabetes in low-resource settings may be at increased hypoglycemia risk due to food insecurity and limited access to glucose monitoring. We aimed to assess hypoglycemia risk associated with sulphonylurea (SU) and insulin therapy in people living with type 2 diabetes in a low-resource sub-Saharan African setting. RESEARCH DESIGN AND METHODS: This study was conducted in the outpatients' diabetes clinics of two hospitals (one rural and one urban) in Uganda. We used blinded continuous glucose monitoring (CGM) and self-report to compare hypoglycemia rates and duration in 179 type 2 diabetes patients treated with sulphonylureas (n=100) and insulin (n=51) in comparison with those treated with metformin only (n=28). CGM-assessed hypoglycemia was defined as minutes per week below 3mmol/L (54mg/dL) and number of hypoglycemic events below 3.0 mmol/L (54 mg/dL) for at least 15 minutes. RESULTS: CGM recorded hypoglycemia was infrequent in SU-treated participants and did not differ from metformin: median minutes/week of glucose
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Author URL.
Shields B, Pang L, Colclough K, Shepherd M, McLean J, Pearson E, Ellard S, Hattersley A (2022). Improvements in awareness and testing have led to a threefold increase over 10 years in the identification of monogenic diabetes in the U.K. Diabetes Care
Grace SL, Bowden J, Walkey HC, Kaur A, Misra S, Shields BM, McKinley TJ, Oliver NS, McDonald TJ, Johnston DG, et al (2022). Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association with Genetic and Clinical Characteristics.
J Clin Endocrinol Metab,
107(12), e4341-e4349.
Abstract:
Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association with Genetic and Clinical Characteristics.
CONTEXT: the importance of the autoantibody level at diagnosis of type 1 diabetes (T1D) is not clear. OBJECTIVE: We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characteristics at diagnosis of T1D. METHODS: We conducted a prospective, cross-sectional study. GADA, IA-2A, and ZnT8A were measured in 1644 individuals with T1D at diagnosis using radiobinding assays. Associations between autoantibody levels and the clinical and genetic characteristics for individuals were assessed in those positive for these autoantibodies. We performed replication in an independent cohort of 449 people with T1D. RESULTS: GADA and IA-2A levels exhibited a bimodal distribution at diagnosis. High GADA level was associated with older age at diagnosis (median 27 years vs 19 years, P = 9 × 10-17), female sex (52% vs 37%, P = 1 × 10-8), other autoimmune diseases (13% vs 6%, P = 3 × 10-6), and HLA-DR3-DQ2 (58% vs 51%, P =. 006). High IA-2A level was associated with younger age of diagnosis (median 17 years vs 23 years, P = 3 × 10-7), HLA-DR4-DQ8 (66% vs 50%, P = 1 × 10-6), and ZnT8A positivity (77% vs 52%, P = 1 × 10-15). We replicated our findings in an independent cohort of 449 people with T1D where autoantibodies were measured using enzyme-linked immunosorbent assays. CONCLUSION: Islet autoantibody levels provide additional information over positivity in T1D at diagnosis. Bimodality of GADA and IA-2A autoantibody levels highlights the novel aspect of heterogeneity of T1D. This may have implications for T1D prediction, treatment, and pathogenesis.
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Author URL.
Shields BM, Angwin CD, Shepherd MH, Britten N, Jones AG, Sattar N, Holman R, Pearson ER, Hattersley AT (2022). Patient preference for second- and third-line therapies in type 2 diabetes: a prespecified secondary endpoint of the TriMaster study. Nature Medicine, 29(2), 384-391.
Shields BM, Dennis JM, Angwin CD, Warren F, Henley WE, Farmer AJ, Sattar N, Holman RR, Jones AG, Pearson ER, et al (2022). Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study. Nature Medicine, 29(2), 376-383.
Eason RJ, Thomas NJ, Hill AV, Knight BA, Carr A, Hattersley AT, McDonald TJ, Shields BM, Jones AG, Grp SS, et al (2022). Routine islet autoantibody testing in clinically diagnosed adult-onset type 1 diabetes can help identify misclassification and guide successful insulin cessation.
DIABETOLOGIA,
65(SUPPL 1), S153-S154.
Author URL.
Osinga JAJ, Derakhshan A, Palomaki GE, Ashoor G, Männistö T, Maraka S, Chen L, Bliddal S, Lu X, Taylor PN, et al (2022). TSH and FT4 Reference Intervals in Pregnancy: a Systematic Review and Individual Participant Data Meta-Analysis.
J Clin Endocrinol Metab,
107(10), 2925-2933.
Abstract:
TSH and FT4 Reference Intervals in Pregnancy: a Systematic Review and Individual Participant Data Meta-Analysis.
CONTEXT: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. OBJECTIVE: (1) to provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. METHODS: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) the individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. RESULTS: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63
198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. CONCLUSION: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.
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Author URL.
Young KG, McGovern AP, Barroso I, Hattersley AT, Jones AG, Shields BM, Thomas NJ, Dennis JM (2022). The impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis.
Diabetologia,
66(2), 300-309.
Abstract:
The impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis
Abstract
. Aims/hypothesis
. Screening programmes can detect cases of undiagnosed diabetes earlier than symptomatic or incidental diagnosis. However, the improvement in time to diagnosis achieved by screening programmes compared with routine clinical care is unclear. We aimed to use the UK Biobank population-based study to provide the first population-based estimate of the reduction in time to diabetes diagnosis that could be achieved by HbA1c-based screening in middle-aged adults.
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. Methods
. We studied UK Biobank participants aged 40–70 years with HbA1c measured at enrolment (but not fed back to participants/clinicians) and linked primary and secondary healthcare data (n=179,923) and identified those with a pre-existing diabetes diagnosis (n=13,077, 7.3%). Among the remaining participants (n=166,846) without a diabetes diagnosis, we used an elevated enrolment HbA1c level (≥48 mmol/mol [≥6.5%]) to identify those with undiagnosed diabetes. For this group, we used Kaplan–Meier analysis to assess the time between enrolment HbA1c measurement and subsequent clinical diabetes diagnosis up to 10 years, and Cox regression to identify clinical factors associated with delayed diabetes diagnosis.
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. Results
. In total, 1.0% (1703/166,846) of participants without a diabetes diagnosis had undiagnosed diabetes based on calibrated HbA1c levels at UK Biobank enrolment, with a median HbA1c level of 51.3 mmol/mol (IQR 49.1–57.2) (6.8% [6.6–7.4]). These participants represented an additional 13.0% of diabetes cases in the study population relative to the 13,077 participants with a diabetes diagnosis. The median time to clinical diagnosis for those with undiagnosed diabetes was 2.2 years, with a median HbA1c at clinical diagnosis of 58.2 mmol/mol (IQR 51.0–80.0) (7.5% [6.8–9.5]). Female participants with lower HbA1c and BMI measurements at enrolment experienced the longest delay to clinical diagnosis.
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. Conclusions/interpretation
. Our population-based study shows that HbA1c screening in adults aged 40–70 years can reduce the time to diabetes diagnosis by a median of 2.2 years compared with routine clinical care. The findings support the use of HbA1c screening to reduce the time for which individuals are living with undiagnosed diabetes.
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. Graphical abstract
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Abstract.
Greiner R, Nyirenda M, Rodgers L, Asiki G, Banda L, Shields B, Hattersley A, Crampin A, Newton R, Jones A, et al (2021). Associations between low HDL, sex and cardiovascular risk markers are substantially different in sub-Saharan Africa and the UK: analysis of four population studies.
BMJ Global Health,
6(5), e005222-e005222.
Abstract:
Associations between low HDL, sex and cardiovascular risk markers are substantially different in sub-Saharan Africa and the UK: analysis of four population studies
IntroductionLow high-density lipoprotein (HDL) is widely used as a marker of cardiovascular disease risk, although this relationship is not causal and is likely mediated through associations with other risk factors. Low HDL is extremely common in sub-Saharan African populations, and this has often been interpreted to indicate that these populations will have increased cardiovascular risk. We aimed to determine whether the association between HDL and other cardiovascular risk factors differed between populations in sub-Saharan Africa and the UK.MethodsWe compared data from adults living in Uganda and Malawi (n=26 216) and in the UK (n=8747). We examined unadjusted and adjusted levels of HDL and applied the WHO recommended cut-offs for prevalence estimates. We used spline and linear regression to assess the relationship between HDL and other cardiovascular risk factors.ResultsHDL was substantially lower in the African than in the European studies (geometric mean 0.9–1.2 mmol/L vs 1.3–1.8 mmol/L), with African prevalence of low HDL as high as 77%. Total cholesterol was also substantially lower (geometric mean 3.3–3.9 mmol/L vs 4.6–5.4 mmol/L). In comparison with European studies the relationship between HDL and adiposity (body mass index, waist to hip ratio) was greatly attenuated in African studies and the relationship with non-HDL cholesterol reversed: in African studies low HDL was associated with lower non-HDL cholesterol. The association between sex and HDL was also different; using the WHO sex-specific definitions, low HDL was substantially more common among women (69%–77%) than men (41%–59%) in Uganda/Malawi.ConclusionThe relationship between HDL and sex, adiposity and non-HDL cholesterol in sub-Saharan Africa is different from European populations. In sub-Saharan Africans low HDL is a marker of low overall cholesterol and sex differences are markedly attenuated. Therefore low HDL in isolation is unlikely to indicate raised cardiovascular risk and the WHO sex-based cut-offs are inappropriate.
Abstract.
Hewat TI, Yau D, Jerome JCS, Laver TW, Houghton JAL, Shields BM, Flanagan SE, Patel KA (2021). Birth weight and diazoxide unresponsiveness strongly predict the likelihood of congenital hyperinsulinism due to a mutation in ABCC8 or KCNJ11.
European Journal of Endocrinology,
185(6), 813-818.
Abstract:
Birth weight and diazoxide unresponsiveness strongly predict the likelihood of congenital hyperinsulinism due to a mutation in ABCC8 or KCNJ11
Objective
Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for the clinical management of the condition. We aimed to determine the clinical features that help to identify KATP-hyperinsulinism at diagnosis.
Design
We studied 761 individuals with KATP-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age. All were referred as part of routine clinical care.
Methods
We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and receiver operator characteristic (ROC) analysis to identify the features that predict KATP-hyperinsulinism.
Results
Higher birth weight, diazoxide unresponsiveness and diagnosis in the first week of life were independently associated with KATP-hyperinsulinism (adjusted odds ratio: 4.5 (95% CI: 3.4–5.9), 0.09 (0.06–0.13) and 3.3 (2.0–5.0) respectively). Birth weight and diazoxide unresponsiveness were additive and highly discriminatory for identifying KATP-hyperinsulinism (ROC area under the curve for birth weight 0.80, diazoxide responsiveness 0.77, and together 0.88, 95% CI: 0.85–0.90). In this study, 86% born large for gestation and 78% born appropriate for gestation and who did not respond to diazoxide treatment had KATP-hyperinsulinism. In contrast, of those individuals born small for gestation, none who were diazoxide responsive and only 4% of those who were diazoxide unresponsive had KATP-hyperinsulinism.
Conclusions
Individuals with hyperinsulinism born appropriate or large for gestation and unresponsive to diazoxide treatment are most likely to have an ABCC8 or KCNJ11 mutation. These patients should be prioritised for genetic testing of KATP channel genes.
Abstract.
Rodgers LR, Hill AV, Dennis JM, Craig Z, May B, Hattersley AT, McDonald TJ, Andrews RC, Jones A, Shields BM, et al (2021). Choice of HbA1c threshold for identifying individuals at high risk of type 2 diabetes and implications for diabetes prevention programmes: a cohort study.
BMC Medicine,
19(1).
Abstract:
Choice of HbA1c threshold for identifying individuals at high risk of type 2 diabetes and implications for diabetes prevention programmes: a cohort study
Abstract
. Background
. Type 2 diabetes (T2D) is common and increasing in prevalence. It is possible to prevent or delay T2D using lifestyle intervention programmes. Entry to these programmes is usually determined by a measure of glycaemia in the ‘intermediate’ range. This paper investigated the relationship between HbA1c and future diabetes risk and determined the impact of varying thresholds to identify those at high risk of developing T2D.
.
. Methods
. We studied 4227 participants without diabetes aged ≥ 40 years recruited to the Exeter 10,000 population cohort in South West England. HbA1c was measured at study recruitment with repeat HbA1c available as part of usual care. Absolute risk of developing diabetes within 5 years, defined by HbA1c ≥ 48 mmol/mol (6.5%), according to baseline HbA1c, was assessed by a flexible parametric survival model.
.
. Results
. The overall absolute 5-year risk (95% CI) of developing T2D in the cohort was 4.2% (3.6, 4.8%). This rose to 7.1% (6.1, 8.2%) in the 56% (n = 2358/4224) of participants classified ‘high-risk’ with HbA1c ≥ 39 mmol/mol (5.7%; ADA criteria). Under IEC criteria, HbA1c ≥ 42 mmol/mol (6.0%), 22% (n = 929/4277) of the cohort was classified high-risk with 5-year risk 14.9% (12.6, 17.2%). Those with the highest HbA1c values (44–47 mmol/mol [6.2–6.4%]) had much higher 5-year risk, 26.4% (22.0, 30.5%) compared with 2.1% (1.5, 2.6%) for 39–41 mmol/mol (5.7–5.9%) and 7.0% (5.4, 8.6%) for 42–43 mmol/mol (6.0–6.1%). Changing the entry criterion to prevention programmes from 39 to 42 mmol/mol (5.7–6.0%) reduced the proportion classified high-risk by 61%, and increased the positive predictive value (PPV) from 5.8 to 12.4% with negligible impact on the negative predictive value (NPV), 99.6% to 99.1%. Increasing the threshold further, to 44 mmol/mol (6.2%), reduced those classified high-risk by 59%, and markedly increased the PPV from 12.4 to 23.2% and had little impact on the NPV (99.1% to 98.5%).
.
. Conclusions
. A large proportion of people are identified as high-risk using current thresholds. Increasing the risk threshold markedly reduces the number of people that would be classified as high-risk and entered into prevention programmes, although this must be balanced against cases missed. Raising the entry threshold would allow limited intervention opportunities to be focused on those most likely to develop T2D.
.
Abstract.
Niwaha AJ, Rodgers LR, Greiner R, Balungi PA, Mwebaze R, McDonald TJ, Hattersley AT, Shields BM, Nyirenda MJ, Jones AG, et al (2021). HbA1c performs well in monitoring glucose control even in populations with high prevalence of medical conditions that may alter its reliability: the OPTIMAL observational multicenter study.
BMJ Open Diabetes Research & Care,
9(1), e002350-e002350.
Abstract:
HbA1c performs well in monitoring glucose control even in populations with high prevalence of medical conditions that may alter its reliability: the OPTIMAL observational multicenter study
IntroductionThe utility of HbA1c (glycosylated hemoglobin) to estimate glycemic control in populations of African and other low-resource countries has been questioned because of high prevalence of other medical conditions that may affect its reliability. Using continuous glucose monitoring (CGM), we aimed to determine the comparative performance of HbA1c, fasting plasma glucose (FPG) (within 5 hours of a meal) and random non-fasting glucose (RPG) in assessing glycemic burden.Research design and methodsWe assessed the performance of HbA1c, FPG and RPG in comparison to CGM mean glucose in 192 Ugandan participants with type 2 diabetes. Analysis was undertaken in all participants, and in subgroups with and without medical conditions reported to affect HbA1c reliability. We then assessed the performance of FPG and RPG, and optimal thresholds, in comparison to HbA1c in participants without medical conditions thought to alter HbA1c reliability.Results32.8% (63/192) of participants had medical conditions that may affect HbA1c reliability: anemia 9.4% (18/192), sickle cell trait and/or hemoglobin C (HbC) 22.4% (43/192), or renal impairment 6.3% (12/192). Despite high prevalence of medical conditions thought to affect HbA1c reliability, HbA1c had the strongest correlation with CGM measured glucose in day-to-day living (0.88, 95% CI 0.84 to 0.91), followed by FPG (0.82, 95% CI 0.76 to 0.86) and RPG (0.76, 95% CI 0.69 to 0.81). Among participants without conditions thought to affect HbA1c reliability, FPG and RPG had a similar diagnostic performance in identifying poor glycemic control defined by a range of HbA1c thresholds. FPG of ≥7.1 mmol/L and RPG of ≥10.5 mmol/L correctly identified 78.2% and 78.8%, respectively, of patients with an HbA1c of ≥7.0%.ConclusionsHbA1c is the optimal test for monitoring glucose control even in low-income and middle-income countries where medical conditions that may alter its reliability are prevalent; FPG and RPG are valuable alternatives where HbA1c is not available.
Abstract.
Moen G-H, Beaumont RN, Grarup N, Sommer C, Shields BM, Lawlor DA, Freathy RM, Evans DM, Warrington NM (2021). Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight.
Int J Epidemiol,
50(1), 179-189.
Abstract:
Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight.
BACKGROUND: Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal. METHODS: We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels. RESULTS: We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [-0.051 (-0.100, -0.003)]. CONCLUSIONS: Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.
Abstract.
Author URL.
Jones AG, McDonald TJ, Shields BM, Hagopian W, Hattersley AT (2021). Latent Autoimmune Diabetes of Adults (LADA) is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes.
Diabetes Care,
44(6), 1243-1251.
Abstract:
Latent Autoimmune Diabetes of Adults (LADA) is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes
Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes–associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test—islet autoantibody measurement—with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes.
Abstract.
Korevaar TIM, Derakhshan A, Taylor PN, Meima M, Chen L, Bliddal S, Carty DM, Meems M, Vaidya B, Shields B, et al (2020). Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity with Preterm Birth: a Systematic Review and Meta-analysis. Obstetrical and Gynecological Survey, 75(1), 10-12.
Carr ALJ, Perry DJ, Lynam AL, Chamala S, Flaxman CS, Sharp SA, Ferrat LA, Jones AG, Beery ML, Jacobsen LM, et al (2020). Histological validation of a type 1 diabetes clinical diagnostic model for classification of diabetes.
Diabetic Medicine,
37(12), 2160-2168.
Abstract:
Histological validation of a type 1 diabetes clinical diagnostic model for classification of diabetes
AbstractAimsMisclassification of diabetes is common due to an overlap in the clinical features of type 1 and type 2 diabetes. Combined diagnostic models incorporating clinical and biomarker information have recently been developed that can aid classification, but they have not been validated using pancreatic pathology. We evaluated a clinical diagnostic model against histologically defined type 1 diabetes.MethodsWe classified cases from the Network for Pancreatic Organ donors with Diabetes (nPOD) biobank as type 1 (n = 111) or non‐type 1 (n = 42) diabetes using histopathology. Type 1 diabetes was defined by lobular loss of insulin‐containing islets along with multiple insulin‐deficient islets. We assessed the discriminative performance of previously described type 1 diabetes diagnostic models, based on clinical features (age at diagnosis, BMI) and biomarker data [autoantibodies, type 1 diabetes genetic risk score (T1D‐GRS)], and singular features for identifying type 1 diabetes by the area under the curve of the receiver operator characteristic (AUC‐ROC).ResultsDiagnostic models validated well against histologically defined type 1 diabetes. The model combining clinical features, islet autoantibodies and T1D‐GRS was strongly discriminative of type 1 diabetes, and performed better than clinical features alone (AUC‐ROC 0.97 vs. 0.95; P = 0.03). Histological classification of type 1 diabetes was concordant with serum C‐peptide [median < 17 pmol/l (limit of detection) vs. 1037 pmol/l in non‐type 1 diabetes; P < 0.0001].ConclusionsOur study provides robust histological evidence that a clinical diagnostic model, combining clinical features and biomarkers, could improve diabetes classification. Our study also provides reassurance that a C‐peptide‐based definition of type 1 diabetes is an appropriate surrogate outcome that can be used in large clinical studies where histological definition is impossible.Parts of this study were presented in abstract form at the Network for Pancreatic Organ Donors Conference, Florida, USA, 19–22 February 2019 and Diabetes UK Professional Conference, Liverpool, UK, 6–8 March 2019.
Abstract.
Lynam AL, Dennis JM, Owen KR, Oram RA, Jones AG, Shields BM, Ferrat LA (2020). Logistic regression has similar performance to optimised machine learning algorithms in a clinical setting: application to the discrimination between type 1 and type 2 diabetes in young adults.
Diagnostic and Prognostic Research,
4(1).
Abstract:
Logistic regression has similar performance to optimised machine learning algorithms in a clinical setting: application to the discrimination between type 1 and type 2 diabetes in young adults
Abstract
Background
There is much interest in the use of prognostic and diagnostic prediction models in all areas of clinical medicine. The use of machine learning to improve prognostic and diagnostic accuracy in this area has been increasing at the expense of classic statistical models. Previous studies have compared performance between these two approaches but their findings are inconsistent and many have limitations. We aimed to compare the discrimination and calibration of seven models built using logistic regression and optimised machine learning algorithms in a clinical setting, where the number of potential predictors is often limited, and externally validate the models.
Methods
We trained models using logistic regression and six commonly used machine learning algorithms to predict if a patient diagnosed with diabetes has type 1 diabetes (versus type 2 diabetes). We used seven predictor variables (age, BMI, GADA islet-autoantibodies, sex, total cholesterol, HDL cholesterol and triglyceride) using a UK cohort of adult participants (aged 18–50 years) with clinically diagnosed diabetes recruited from primary and secondary care (n = 960, 14% with type 1 diabetes). Discrimination performance (ROC AUC), calibration and decision curve analysis of each approach was compared in a separate external validation dataset (n = 504, 21% with type 1 diabetes).
Results
Average performance obtained in internal validation was similar in all models (ROC AUC ≥ 0.94). In external validation, there were very modest reductions in discrimination with AUC ROC remaining ≥ 0.93 for all methods. Logistic regression had the numerically highest value in external validation (ROC AUC 0.95). Logistic regression had good performance in terms of calibration and decision curve analysis. Neural network and gradient boosting machine had the best calibration performance. Both logistic regression and support vector machine had good decision curve analysis for clinical useful threshold probabilities.
Conclusion
Logistic regression performed as well as optimised machine algorithms to classify patients with type 1 and type 2 diabetes. This study highlights the utility of comparing traditional regression modelling to machine learning, particularly when using a small number of well understood, strong predictor variables.
Abstract.
P B, TJ M, BA K, SE F, M L, SR S, BM S, S H, MH S, RC A, et al (2020). Patterns of post-meal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-K ATP -channel pathways.
Agbaje OF, Coleman RL, Hattersley AT, Jones AG, Pearson ER, Shields BM, Holman RR (2020). Predicting post one-year durability of glucose-lowering monotherapies in patients with newly-diagnosed type 2 diabetes mellitus – a MASTERMIND precision medicine approach (UKPDS 87). Diabetes Research and Clinical Practice, 166, 108333-108333.
Rodgers LR, Dennis JM, Shields BM, Mounce L, Fisher I, Hattersley AT, Henley WE (2020). Prior event rate ratio adjustment produced estimates consistent with randomized trial: a diabetes case study. Journal of Clinical Epidemiology, 122, 78-86.
McGovern AP, Hogg M, Shields BM, Sattar NA, Holman RR, Pearson ER, Hattersley AT, Jones AG, Dennis JM (2020). Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation.
BMJ Open Diabetes Research & Care,
8(1), e001238-e001238.
Abstract:
Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation
IntroductionTo identify risk factors, absolute risk, and impact on treatment discontinuation of genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT2i).Research design and methodsWe assessed the relationship between baseline characteristics and genital infection in 21 004 people with type 2 diabetes initiating SGLT2i and 55 471 controls initiating dipeptidyl peptidase-4 inhibitors (DPP4i) in a UK primary care database. We assessed absolute risk of infection in those with key risk factors and the association between early genital infection and treatment discontinuation.ResultsGenital infection was substantially more common in those treated with SGLT2i (8.1% within 1 year) than DPP4i (1.8%). Key predictors of infection with SGLT2i were female sex (HR 3.64; 95% CI 3.23 to 4.11) and history of genital infection; <1 year before initiation (HR 4.38; 3.73 to 5.13), 1–5 years (HR 3.04; 2.64 to 3.51), and >5 years (HR 1.79; 1.55 to 2.07). Baseline HbA1c was not associated with infection risk for SGLT2i, in contrast to DPP4i where risk increased with higher HbA1c. One-year absolute risk of genital infection with SGLT2i was highest for those with a history of prior infection (females 23.7%, males 12.1%), compared with those without (females 10.8%, males 2.7%). Early genital infection was associated with a similar discontinuation risk for SGLT2i (HR 1.48; 1.21–1.80) and DPP4i (HR 1.58; 1.21–2.07).ConclusionsFemale sex and history of prior infection are simple features that can identify subgroups at greatly increased risk of genital infections with SGLT2i therapy. These data can be used to risk-stratify patients. High HbA1c is not a risk factor for genital infections with SGLT2i.
Abstract.
Jones AG, Shields BM, Dennis JM, Hattersley AT, McDonald TJ, Thomas NJ (2020). The challenge of diagnosing type 1 diabetes in older adults.
Diabet Med,
37(10), 1781-1782.
Author URL.
Angwin C, Jenkinson C, Jones A, Jennison C, Henley W, Farmer A, Sattar N, Holman RR, Pearson E, Shields B, et al (2020). TriMaster: randomised double-blind crossover study of a DPP4 inhibitor, SGLT2 inhibitor and thiazolidinedione as second-line or third-line therapy in patients with type 2 diabetes who have suboptimal glycaemic control on metformin treatment with or without a sulfonylurea—a MASTERMIND study protocol.
BMJ Open,
10(12), e042784-e042784.
Abstract:
TriMaster: randomised double-blind crossover study of a DPP4 inhibitor, SGLT2 inhibitor and thiazolidinedione as second-line or third-line therapy in patients with type 2 diabetes who have suboptimal glycaemic control on metformin treatment with or without a sulfonylurea—a MASTERMIND study protocol
IntroductionPharmaceutical treatment options for patients with type 2 diabetes mellitus (T2DM) have increased to include multiple classes of oral glucose-lowering agents but without accompanying guidance on which of these may most benefit individual patients. Clinicians lack information for treatment intensification after first-line metformin therapy. Stratifying patients by simple clinical characteristics may improve care by targeting treatment options to those in whom they are most effective. This academically designed and run three-way crossover trial aims to test a stratification approach using three standard oral glucose-lowering agents.Methods and analysisTriMaster is a randomised, double-blind, crossover trial taking place at up to 25 clinical sites across England, Scotland and Wales. 520 patients with T2DM treated with either metformin alone, or metformin and a sulfonylurea who have glycated haemoglobin (HbA1c) >58 mmol/mol will be randomised to receive 16 weeks each of a dipeptidyl peptidase‐4 inhibitor, sodium-glucose co-transporter-2 inhibitor and thiazolidinedione in random order. Participants will be assessed at the end of each treatment period, providing clinical and biochemical data, and their experience of side effects. Participant preference will be assessed on completion of all three treatments. The primary endpoint is HbA1c after 4 months of therapy (allowing a range of 12–18 weeks for analysis). Secondary endpoints include participant-reported preference between the three treatments, tolerability and prevalence of side effects.Ethical approvalThis study was approved by National Health Service Health Research Authority Research Ethics Committee South Central—Oxford A, study 16/SC/0147. Written informed consent will be obtained from all participants. Results will be submitted to a peer-reviewed journal and presented at relevant scientific meetings. A lay summary of results will be made available to all participants.Trial registration numbers12039221; 2015-002790-38 and NCT02653209.
Abstract.
Grubb AL, McDonald TJ, Rutters F, Donnelly LA, Hattersley AT, Oram RA, Palmer CNA, van der Heijden AA, Carr F, Elders PJM, et al (2019). A Type 1 Diabetes Genetic Risk Score can Identify Patients with GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy.
Diabetes Care,
42(2), 208-214.
Abstract:
A Type 1 Diabetes Genetic Risk Score can Identify Patients with GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy.
OBJECTIVE: Progression to insulin therapy in clinically diagnosed type 2 diabetes is highly variable. GAD65 autoantibodies (GADA) are associated with faster progression, but their predictive value is limited. We aimed to determine if a type 1 diabetes genetic risk score (T1D GRS) could predict rapid progression to insulin treatment over and above GADA testing. RESEARCH DESIGN AND METHODS: We examined the relationship between T1D GRS, GADA (negative or positive), and rapid insulin requirement (within 5 years) using Kaplan-Meier survival analysis and Cox regression in 8,608 participants with clinical type 2 diabetes (onset >35 years and treated without insulin for ≥6 months). T1D GRS was both analyzed continuously (as standardized scores) and categorized based on previously reported centiles of a population with type 1 diabetes (50th [high]). RESULTS: in GADA-positive participants (3.3%), those with higher T1D GRS progressed to insulin more quickly: probability of insulin requirement at 5 years (95% CI): 47.9% (35.0%, 62.78%) (high T1D GRS) vs. 27.6% (20.5%, 36.5%) (medium T1D GRS) vs. 17.6% (11.2%, 27.2%) (low T1D GRS); P = 0.001. In contrast, T1D GRS did not predict rapid insulin requirement in GADA-negative participants (P = 0.4). In Cox regression analysis with adjustment for age of diagnosis, BMI, and cohort, T1D GRS was independently associated with time to insulin only in the presence of GADA: hazard ratio per SD increase was 1.48 (1.15, 1.90); P = 0.002. CONCLUSIONS: a T1D GRS alters the clinical implications of a positive GADA test in patients with clinical type 2 diabetes and is independent of and additive to clinical features.
Abstract.
Author URL.
Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar TIM, Derakhshan A, Taylor PN, Meima M, Chen L, Bliddal S, Carty DM, Meems M, Vaidya B, et al (2019). Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity with Preterm Birth: a Systematic Review and Meta-analysis.
JAMA,
322(7), 632-641.
Abstract:
Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity with Preterm Birth: a Systematic Review and Meta-analysis.
IMPORTANCE: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. OBJECTIVE: to study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. DATA SOURCES AND STUDY SELECTION: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. DATA EXTRACTION AND SYNTHESIS: the primary authors provided individual participant data that were analyzed using mixed-effects models. MAIN OUTCOMES AND MEASURES: the primary outcome was preterm birth (
Abstract.
Author URL.
Dennis JM, Shields BM, Henley WE, Jones AG, Hattersley AT (2019). Clusters provide a better holistic view of type 2 diabetes than simple clinical features - Authors' reply.
Lancet Diabetes Endocrinol,
7(9).
Author URL.
Dennis J, Shields B, Henley W, Jones A, Hattersley A (2019). Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared to models based on simple clinical features: an evaluation using clinical trial data. Lancet Diabetes and Endocrinology
Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland Ø, Laurin C, Bacelis J, Peng S, Hao K, Feenstra B, et al (2019). Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Nat Genet,
51(5), 804-814.
Abstract:
Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
Abstract.
Author URL.
Bowman P, McDonald TJ, Knight BA, Flanagan SE, Leveridge M, Spaull SR, Shields BM, Hammersley S, Shepherd MH, Andrews RC, et al (2019). Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-K ATP -channel pathways.
BMJ Open Diabetes Research and Care,
7(1).
Abstract:
Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-K ATP -channel pathways
Objective Insulin secretion in sulfonylurea-treated KCNJ11 permanent neonatal diabetes mellitus (PNDM) is thought to be mediated predominantly through amplifying non-K ATP -channel pathways such as incretins. Affected individuals report symptoms of postprandial hypoglycemia after eating protein/fat-rich foods. We aimed to assess the physiological response to carbohydrate and protein/fat in people with sulfonylurea-treated KCNJ11 PNDM. Research design and methods 5 adults with sulfonylurea-treated KCNJ11 PNDM and five age, sex and body mass index-matched controls without diabetes had a high-carbohydrate and high-protein/fat meal on two separate mornings. Insulin(i) and glucose(g) were measured at baseline then regularly over 4 hours after the meal. Total area under the curve (tAUC) for insulin and glucose was calculated over 4 hours and compared between meals in controls and KCNJ11 cases. Results in controls, glucose values after carbohydrate and protein/fat were similar (median glucose tAUC 0-4h 21.4 vs 19.7 mmol/L, p=0.08). In KCNJ11 cases glucose levels were higher after carbohydrate than after protein/fat (median glucose tAUC 0-4h 58.1 vs 31.3 mmol/L, p=0.04). These different glycemic responses reflected different patterns of insulin secretion: in controls, insulin secretion was greatly increased after carbohydrate versus protein/fat (median insulin tAUC 0-4h 727 vs 335 pmol/L, p=0.04), but in KCNJ11 cases insulin secretion was similar after carbohydrate and protein/fat (median insulin tAUC 0-4h 327 vs 378 pmol/L, p=0.50). Conclusions Individuals with sulfonylurea-treated KCNJ11 PNDM produce similar levels of insulin in response to both carbohydrate and protein/fat meals despite carbohydrate resulting in much higher glucose levels and protein/fat resulting in relatively low glucose levels. This suggests in an inability to modulate insulin secretion in response to glucose levels, consistent with a dependence on non-K ATP pathways for insulin secretion. Trial registration number NCT02921906.
Abstract.
Marren SM, Hammersley S, McDonald TJ, Shields BM, Knight BA, Hill A, Bolt R, Tree TI, Roep BO, Hattersley AT, et al (2019). Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?.
Diabet Med,
36(9), 1092-1099.
Abstract:
Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?
AIMS: Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c , hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C-peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes. METHODS: We conducted a cross-sectional case-control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C-peptide after a mixed-meal tolerance test. We compared self-reported hypoglycaemia (n = 160), HbA1c , insulin dose and microvascular complications (n = 140) in those with preserved and low C-peptide. RESULTS: Stimulated median (IQR) C-peptide was 114 (43, 273) pmol/l and
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Author URL.
Dennis JM, Henley WE, McGovern AP, Farmer AJ, Sattar N, Holman RR, Pearson ER, Hattersley AT, Shields BM, Jones AG, et al (2019). Time trends in prescribing of type 2 diabetes drugs, glycaemic response and risk factors: a retrospective analysis of primary care data, 2010-2017.
Diabetes Obes Metab,
21(7), 1576-1584.
Abstract:
Time trends in prescribing of type 2 diabetes drugs, glycaemic response and risk factors: a retrospective analysis of primary care data, 2010-2017.
AIM: to describe population-level time trends in prescribing patterns of type 2 diabetes therapy, and in short-term clinical outcomes (glycated haemoglobin [HbA1c], weight, blood pressure, hypoglycaemia and treatment discontinuation) after initiating new therapy. MATERIALS AND METHODS: We studied 81 532 people with type 2 diabetes initiating a first- to fourth-line drug in primary care between 2010 and 2017 inclusive in United Kingdom electronic health records (Clinical Practice Research Datalink). Trends in new prescriptions and subsequent 6- and 12-month adjusted changes in glycaemic response (reduction in HbA1c), weight, blood pressure and rates of hypoglycaemia and treatment discontinuation were examined. RESULTS: Use of dipeptidyl peptidase-4 inhibitors as second-line therapy near doubled (41% of new prescriptions in 2017 vs. 22% in 2010), replacing sulphonylureas as the most common second-line drug (29% in 2017 vs. 53% in 2010). Sodium-glucose co-transporter-2 inhibitors, introduced in 2013, comprised 17% of new first- to fourth-line prescriptions by 2017. First-line use of metformin remained stable (91% of new prescriptions in 2017 vs. 91% in 2010). Over the study period there was little change in average glycaemic response and in the proportion of people discontinuing treatment. There was a modest reduction in weight after initiating second- and third-line therapy (improvement in weight change 2017 vs. 2010 for second-line therapy: -1.5 kg, 95% confidence interval [CI] -1.9, -1.1; P
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McGovern AP, Dennis JM, Shields BM, Hattersley AT, Pearson ER, Jones AG, MASTERMIND Consortium (2019). What to do with diabetes therapies when HbA1c lowering is inadequate: add, switch, or continue? a MASTERMIND study.
BMC Med,
17(1).
Abstract:
What to do with diabetes therapies when HbA1c lowering is inadequate: add, switch, or continue? a MASTERMIND study.
BACKGROUND: it is unclear what to do when people with type 2 diabetes have had no or a limited glycemic response to a recently introduced medication. Intra-individual HbA1c variability can obscure true response. Some guidelines suggest stopping apparently ineffective therapy, but no studies have addressed this issue. METHODS: in a retrospective cohort analysis using the UK Clinical Practice Research Datalink (CPRD), we assessed the outcome of 55,530 patients with type 2 diabetes starting their second or third non-insulin glucose-lowering medication, with a baseline HbA1c > 58 mmol/mol (7.5%). For those with no HbA1c improvement or a limited response at 6 months (HbA1c fall
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Patel KA, Weedon MN, Shields BM, Pearson ER, Hattersley AT, McDonald TJ, UNITED study team (2019). Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score can Exclude Individuals with Type 1 Diabetes from Inappropriate Genetic Testing for Monogenic Diabetes.
Diabetes Care,
42(2), e16-e17.
Author URL.
Shepherd MH, Shields BM, Hudson M, Pearson ER, Hyde C, Ellard S, Hattersley AT, Patel KA (2018). A UK nationwide prospective study of treatment change in MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after discontinuing insulin and metformin.
Diabetologia,
61(12), 2520-2527.
Abstract:
A UK nationwide prospective study of treatment change in MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after discontinuing insulin and metformin
Aims/hypothesis: Treatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA 1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years. Methods: This was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate. Results: a total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA 1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years’ follow-up without treatment, p = 0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA 1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA 1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m 2 ) at the time of genetic diagnosis, compared with individuals (n = 23/36) with an HbA 1c >58 mmol/mol (>7.5%) (or 69 mmol/mol (>8.5%) at the time of genetic diagnosis. Conclusions/interpretation: in participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA 1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA 1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA 1c.
Abstract.
Shields BM, McDonald TJ, Oram R, Hill A, Hudson M, Leete P, Pearson ER, Richardson SJ, Morgan NG, Hattersley AT, et al (2018). C-peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase.
Diabetes Care,
41(7), 1486-1492.
Abstract:
C-peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase
OBJECTIVE the decline in C-peptide in the 5 years after diagnosis of type 1 diabetes has been well studied, but little is known about the longer-term trajectory. We aimed to examine the association between log-transformed C-peptide levels and the duration of diabetes up to 40 years after diagnosis. RESEARCH DESIGN AND METHODS We assessed the pattern of association between urinary C-peptide/creatinine ratio (UCPCR) and duration of diabetes in cross-sectional data from 1,549 individuals with type 1 diabetes using nonlinear regression approaches. Findings were replicated in longitudinal follow-up data for both UCPCR (n = 161 individuals, 326 observations) and plasma C-peptide (n = 93 individuals, 473 observations). RESULTS We identified two clear phases of C-peptide decline: an initial exponential fall over 7 years (47% decrease/year [95% CI 251, 243]) followed by a stable period thereafter (10.07%/year [21.3, 11.5]). The two phases had similar durations and slopes in patients above and below the median age at diagnosis (10.8 years), although levels were lower in the younger patients irrespective of duration. Patterns were consistent in both longitudinal UCPCR (n = 162; £7 years duration: 248%/year [255, 238]; >7 years duration 20.1% [24.1, 13.9]) and plasma C-peptide (n = 93; >7 years duration only: 22.6% [26.7, 11.5]). CONCLUSIONS These data support two clear phases of C-peptide decline: an initial exponential fall over a 7-year period, followed by a prolonged stabilization where C-peptide levels no longer decline. Understanding the pathophysiological and immunological differences between these two phases will give crucial insights into understanding b-cell survival.
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Knight BA, Shields BM, He X, Pearce EN, Braverman LE, Sturley R, Vaidya B (2018). Effect of perchlorate and thiocyanate exposure on thyroid function of pregnant women from South-West England: a cohort study.
Thyroid Research,
11(1).
Abstract:
Effect of perchlorate and thiocyanate exposure on thyroid function of pregnant women from South-West England: a cohort study
Background: Iodine is important for thyroid hormone synthesis, and iodine deficiency in pregnancy may impair fetal neurological development. As perchlorate and thiocyanate inhibit sodium-iodide symporter reducing the transport of iodine from circulation into the thyroid follicular cells, environmental exposure to these substances in pregnancy may impair maternal thyroid hormone synthesis. We aimed to explore the impact of perchlorate and thiocyanate exposure on thyroid status in a cohort of pregnant mothers from South West England. Methods: Urine samples were obtained from 308 women participating in a study of breech presentation in late pregnancy. They had no known thyroid disease and a singleton pregnancy at 36-38 weeks gestation. Samples were analysed for urinary concentrations of iodine (UIC), perchlorate (UPC) and thiocyanate (UTC). Blood samples were taken for free T4 (FT4), thyrotropin (TSH) and thyroid peroxidase antibodies (TPO-Ab). Baseline data included age, parity, smoking status, ethnicity and BMI at booking. Following delivery, data on offspring's sex, gestational age at birth and birthweight were collected. Results: Participants had a mean (SD) age 31 (5) years, median (IQR) BMI 24.4 (22.0, 28.3) kg/m2, 42% were primiparous, 10% were smokers, and 96% were Caucasian. Median UIC was 88 μg/l, and 174/308 (57%) women had UIC < 100 μg/l. Log transformed UPC negatively correlated with FT4, but not with TSH, in the whole cohort (r = - 0.12, p = 0.03) and in the subgroup of women with UIC < 100 μg/l (r = - 0.15, p = 0.04). Regression analysis with the potential confounders (TPO-Ab status, UIC and UTC) identified UPC to be negatively associated with FT4 (p = 0.01). There was no correlation between UTC and FT4 or TSH. Maternal UPC or UTC was not associated with offspring birthweight. Conclusion: Environmental perchlorate exposure is negatively associated with circulating FT4 levels in third trimester pregnant women. This may have an adverse impact on neurocognitive development of the fetus.
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Dennis JM, Shields BM, Jones AG, Pearson ER, Hattersley AT, Henley WE, MASTERMIND consortium (2018). Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes: a joint modeling approach.
Clin Epidemiol,
10, 1869-1877.
Abstract:
Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes: a joint modeling approach.
OBJECTIVE: Precision medicine drug therapy seeks to maximize efficacy and minimize harm for individual patients. This will be difficult if drug response and side effects are positively associated, meaning that patients likely to respond best are at increased risk of side effects. We applied joint longitudinal-survival models to evaluate associations between drug response (longitudinal outcome) and the risk of side effects (survival outcome) for patients initiating type 2 diabetes therapy. STUDY DESIGN AND SETTING: Participants were randomized to metformin (MFN), sulfonylurea (SU), or thiazolidinedione (TZD) therapy in the a Diabetes Outcome Progression Trial (ADOPT) drug efficacy trial (n=4,351). Joint models were parameterized for 1) current HbA1c response (change from baseline in HbA1c) and 2) cumulative HbA1c response (total HbA1c change). RESULTS: with MFN, greater HbA1c response did not increase the risk of gastrointestinal events (HR per 1% absolute greater current response 0.82 [95% CI 0.67, 1.01]; HR per 1% higher cumulative response 0.90 [95% CI 0.81, 1.00]). With SU, greater current response was associated with an increased risk of hypoglycemia (HR 1.41 [95% CI 1.04, 1.91]). With TZD, greater response was associated with an increased risk of edema (current HR 1.45 [95% CI 1.05, 2.01]; cumulative 1.22 [95% CI 1.07, 1.38]) but not fracture. CONCLUSION: Joint modeling provides a useful framework to evaluate the association between response to a drug and the risk of developing side effects. There may be great potential for widespread application of joint modeling to evaluate the risks and benefits of both new and established medications.
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Author URL.
Clissold RL, Fulford J, Hudson M, Shields BM, McDonald TJ, Ellard S, Hattersley AT, Bingham C (2018). Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic.
Clin Kidney J,
11(4), 453-458.
Abstract:
Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic.
BACKGROUND: Heterozygous mutations in the HNF1B gene are the most common monogenic cause of developmental kidney disease. Extrarenal phenotypes frequently occur, including diabetes mellitus and pancreatic hypoplasia; the latter is associated with subclinical exocrine dysfunction. We measured faecal elastase-1 in patients with HNF1B-associated disease regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. METHODS: Faecal elastase-1 was measured in 29 patients with a known HNF1B mutation. We defined a low faecal elastase-1 concentration based on the 2.5 percentile of 99 healthy control individuals (410 μg/g stool). Symptoms related to pancreatic exocrine dysfunction were assessed and a subset of the HNF1B cohort (n = 6) underwent pancreatic imaging. RESULTS: Faecal elastase-1 was below the 2.5 percentile of the control cohort in 18/29 (62%) patients with HNF1B-associated renal disease. A total of 8/29 (28%) had a measurement suggestive of exocrine pancreatic insufficiency at
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Hughes AE, Nodzenski M, Beaumont RN, Talbot O, Shields BM, Scholtens DM, Knight BA, Lowe WL, Hattersley AT, Freathy RM, et al (2018). Fetal Genotype and Maternal Glucose Have Independent and Additive Effects on Birth Weight.
Diabetes,
67(5), 1024-1029.
Abstract:
Fetal Genotype and Maternal Glucose Have Independent and Additive Effects on Birth Weight.
Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.
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NJ T, SE J, MN W, BM S, RA O, AT H (2018). Frequency and phenotype of T1DM in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank.
Thomas NJ, Jones SE, Weedon MN, Shields BM, Oram RA, Hattersley AT (2018). Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank.
The Lancet Diabetes and Endocrinology,
6(2), 122-129.
Abstract:
Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank
Background: Type 1 diabetes is typically considered a disease of children and young adults. Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes. It is not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years. We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life. Methods: in this cross-sectional analysis, we used a type 1 diabetes genetic risk score based on 29 common variants to identify individuals of white European descent in UK Biobank in the half of the population with high or low genetic susceptibility to type 1 diabetes. We used Kaplan-Meier analysis to evaluate the number of cases of diabetes in both groups in the first six decades of life. We genetically defined type 1 diabetes as the additional cases of diabetes that occurred in the high genetic susceptibility group compared with the low genetic susceptibility group. All remaining cases were defined as type 2 diabetes. We assessed the clinical characteristics of the groups with genetically defined type 1 or type 2 diabetes. Findings: 13 250 (3·5%) of 379 511 white European individuals in UK Biobank had developed diabetes in the first six decades of life. 1286 more cases of diabetes were in the half of the population with high genetic susceptibility to type 1 diabetes than in the half of the population with low genetic susceptibility. These genetically defined cases of type 1 diabetes were distributed across all ages of diagnosis; 537 (42%) were in individuals diagnosed when aged 31–60 years, representing 4% (537/12 233) of all diabetes cases diagnosed after age 30 years. The clinical characteristics of the group diagnosed with type 1 diabetes when aged 31–60 years were similar to the clinical characteristics of the group diagnosed with type 1 diabetes when aged 30 years or younger. For individuals diagnosed with diabetes when aged 31–60 years, the clinical characteristics of type 1 diabetes differed from those of type 2 diabetes: they had a lower BMI (27·4 kg/m2 [95% CI 26·7–28·0] vs 32·4 kg/m2 [32·2–32·5]; p
Abstract.
Thomas NJ, Jones SE, Weedon MN, Shields BM, Hattersley AT, Oram RA (2018). Genetic risk scores in adult-onset type 1 diabetes – Authors' reply. The Lancet Diabetes and Endocrinology, 6(3).
Dennis JM, Shields BM, Hill AV, Knight BA, McDonald TJ, Rodgers LR, Weedon MN, Henley WE, Sattar N, Holman RR, et al (2018). Precision medicine in type 2 Diabetes: Clinical markers of insulin resistance are associated with altered short- a nd long-term glycemic response to DPP-4 inhibitor therapy.
Diabetes Care,
41(4), 705-712.
Abstract:
Precision medicine in type 2 Diabetes: Clinical markers of insulin resistance are associated with altered short- a nd long-term glycemic response to DPP-4 inhibitor therapy
OBJECTIVE a precision approach to type 2 diabetes therapy would aim to target treatment accorDing to patient characteristics. We examined if measures of insulin resistance and secretion were associated with glycemic response to dipeptidyl peptidase 4 (DPP-4) inhibitor therapy. RESEARCH DESIGN AND METHODS We evaluated whether markers of insulin resistance and insulin secretion were associated with 6-month glycemic response in a prospective study of noninsulintreated participants starting DPP-4 inhibitor therapy (Predicting Response to Incretin Based Agents [PRIBA] study; n = 254), with replication for routinely availablemarkers in U.K. electronic health care records (Clinical Practice Research Datalink [CPRD]; n = 23,001). In CPRD, we evaluated associations between baseline markers and 3-year durability of response. To test the specificity of findings, we repeated analyses for glucagon-like peptide 1 (GLP-1) receptor agonists (PRIBA, n = 339; CPRD, n = 4,464). RESULTS in PRIBA, markers of higher insulin resistance (higher fasting C-peptide [P = 0.03], HOMA2 insulin resistance [P = 0.01], and triglycerides [P
Abstract.
Hope SV, Knight BA, Shields BM, Hill AV, Choudhary P, Strain WD, McDonald TJ, Jones AG (2018). Random non-fasting C-peptide testing can identify patients with insulin-treated type 2 diabetes at high risk of hypoglycaemia.
Diabetologia,
61(1), 66-74.
Abstract:
Random non-fasting C-peptide testing can identify patients with insulin-treated type 2 diabetes at high risk of hypoglycaemia
Aims/hypothesis: the aim of this study was to determine whether random non-fasting C-peptide (rCP) measurement can be used to assess hypoglycaemia risk in insulin-treated type 2 diabetes. Methods: We compared continuous glucose monitoring-assessed SD of blood glucose and hypoglycaemia duration in 17 patients with insulin-treated type 2 diabetes and severe insulin deficiency (rCP 600 pmol/l). We then assessed the relationship between rCP and questionnaire-based measures of hypoglycaemia in 256 patients with insulin-treated type 2 diabetes and a comparison group of 209 individuals with type 1 diabetes. Results: Continuous glucose monitoring (CGM)-assessed glucose variability and hypoglycaemia was greater in individuals with rCP
Abstract.
Dennis JM, Henley WE, Weedon MN, Lonergan M, Rodgers LR, Jones AG, Hamilton WT, Sattar N, Janmohamed S, Holman RR, et al (2018). Sex and BMI alter the benefits and risks of sulfonylureas and thiazolidinediones in type 2 diabetes: a framework for evaluating stratification using routine clinical and individual trial data.
Diabetes Care,
41(9), 1844-1853.
Abstract:
Sex and BMI alter the benefits and risks of sulfonylureas and thiazolidinediones in type 2 diabetes: a framework for evaluating stratification using routine clinical and individual trial data
OBJECTIVE: the choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones. RESEARCH DESIGN AND METHODS: We studied 22, 379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2, 725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2, 222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1, 977). RESULTS: in CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups. CONCLUSIONS: Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.
Abstract.
Curtis HJ, Dennis JM, Shields BM, Walker AJ, Bacon S, Hattersley AT, Jones AG, Goldacre B (2018). Time trends and geographical variation in prescribing of drugs for diabetes in England from 1998 to 2017.
Diabetes Obes Metab,
20(9), 2159-2168.
Abstract:
Time trends and geographical variation in prescribing of drugs for diabetes in England from 1998 to 2017.
AIMS: to measure the variation in prescribing of second-line non-insulin diabetes drugs. MATERIALS AND METHODS: We evaluated time trends for the period 1998 to 2016, using England's publicly available prescribing datasets, and stratified these by the order in which they were prescribed to patients using the Clinical Practice Research Datalink. We calculated the proportion of each class of diabetes drug as a percentage of the total per year. We evaluated geographical variation in prescribing using general practice-level data for the latest 12 months (to August 2017), with aggregation to Clinical Commissioning Groups. We calculated percentiles and ranges, and plotted maps. RESULTS: Prescribing of therapy after metformin is changing rapidly. Dipeptidyl peptidase-4 (DPP-4) inhibitor use has increased markedly, with DPP-4 inhibitors now the most common second-line drug (43% prescriptions in 2016). The use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors also increased rapidly (14% new second-line, 27% new third-line prescriptions in 2016). There was wide geographical variation in choice of therapies and average spend per patient. In contrast, metformin was consistently used as a first-line treatment in accordance with guidelines. CONCLUSIONS: in England there is extensive geographical variation in the prescribing of diabetes drugs after metformin, and increasing use of higher-cost DPP-4 inhibitors and SGLT-2 inhibitors compared with low-cost sulphonylureas. Our findings strongly support the case for comparative effectiveness trials of current diabetes drugs.
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Author URL.
Thomas N, Grubb A, McDonald T, Hill A, Weedon M, Oram R, Hattersley A, Jones A (2018). Type 1 diabetes leading to severe insulin deficiency occurs after 30 years of age and is commonly treated as type 2 diabetes in clinical practice.
DIABETOLOGIA,
61, S152-S152.
Author URL.
Hope SV, Taylor PJ, Shields BM, Hattersley AT, Hamilton W (2017). Are we missing hypoglycaemia?. Elderly patients with insulin-treated diabetes present to. primary care frequently with non-specific symptoms. associated with hypoglycaemia. Primary Care Diabetes
Rodgers LR, Weedon MN, Henley WE, Hattersley AT, Shields BM (2017). Cohort profile for the MASTERMIND study: using the Clinical Practice Research Datalink (CPRD) to investigate stratification of response to treatment in patients with type 2 diabetes.
BMJ Open,
7(10).
Abstract:
Cohort profile for the MASTERMIND study: using the Clinical Practice Research Datalink (CPRD) to investigate stratification of response to treatment in patients with type 2 diabetes.
PURPOSE: This is a retrospective cohort study using observational data from anonymised primary care records. We identify and extract all patients with type 2 diabetes and associated clinical data from the Clinical Practice Research Datalink (CPRD) to inform models of disease progression and stratification of treatment. PARTICIPANTS: Data were extracted from CPRD on 8 August 2016. The initial data set contained all patients (n=313 485) in the database who had received a type 2 diabetes medication. Criteria were applied to identify and exclude those with type 1 diabetes, polycystic ovarian syndrome or other forms of diabetes (n=40 204), and for data quality control (n=12). We identified 251 338 patients for inclusion in future analyses of diabetes progression and treatment response. FINDINGS TO DATE: for 6-month response to treatment, measured by change in glycated haemoglobin (HbA1c), we have 91 765 patients with 119 785 treatment response episodes. The greatest impact on reduction of HbA1c occurs with first-line and second-line treatments, metformin and sulfonylurea. Patients moving to third-line treatments tend to have greater weights and higher body mass index. We have investigated the impact of non-adherence to commonly used glucose-lowering medications on HbA1c. For baseline-adjusted HbA1c change over 1 year, non-adherent patients had lower HbA1c reductions than adherent patients, with mean and 95% CI of -4.4 (-4.7 to -4.0) mmol/mol (-0.40 (-0.43 to -0.37) %). FUTURE PLANS: Findings from studies using these data will help inform future treatment plans and guidelines. Additional data are added with updates from CPRD. This will increase the numbers of patients on newer medications and add more data on those already receiving treatment. There are several ongoing studies investigating different hypotheses regarding differential response to treatment and progression of diabetes. For side effects, links to Hospital Episode Statistics data, where severe events such as hypoglycaemia will be recorded, will also be explored.
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Knight BA, Shields BM, He X, Pearce EN, Braverman LE, Sturley R, Vaidya B (2017). Iodine deficiency amongst pregnant women in South-West England.
Clin Endocrinol (Oxf),
86(3), 451-455.
Abstract:
Iodine deficiency amongst pregnant women in South-West England.
INTRODUCTION: Iodine deficiency in pregnancy may impair foetal neurological development. The UK population is generally thought to be iodine sufficient; however, recent studies have questioned this assumption. Our study aimed to explore the prevalence of iodine deficiency in a cohort of pregnant mothers from South-West England. METHODS: Urine samples were obtained from 308 women participating in a study of breech presentation in late pregnancy. They had no known thyroid disease and a singleton pregnancy at 36-38 weeks' gestation. Samples were analysed for urinary iodine concentrations (UIC). Baseline data included age, parity, smoking status, ethnicity, body mass index (BMI) at booking, prenatal vitamin use and a dietary questionnaire. There was no difference in median UIC between women with (n = 156) or without (n = 152) a breech presentation (P = 0·3), so subsequent analyses were carried out as a combined group. RESULTS: Participants had a mean (SD) age 31(5) years, median (IQR) BMI 24·4 (22·0, 28·3) kg/m2 ; 42% were primiparous, 10% smoked during pregnancy, and 35% took iodine-containing vitamins. Ninety-six per cent were Caucasian. Median (IQR) UIC was 88·0 (54·3, 157·5) μg/l, which is consistent with iodine deficiency by WHO criteria. A total of 224/308 (73%) of women had UIC values
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Bartalena L, Fliers E, Hellen N, Taylor PN, Lacey A, Thayer D, Yusof MD, Tabasum A, Muller I, Marsh L, et al (2017). Meeting abstracts from the 64th British Thyroid Association Annual Meeting. Thyroid Research, 10(Suppl 1).
Knight B, Shields B, Pearce E, Braverman L, He X, Sturley R, Vaidya B (2017). Perchlorate exposure affects thyroid function in third trimester pregnant women from South-West England. Endocrine Abstracts
Shields BM, Shepherd M, Hudson M, McDonald TJ, Colclough K, Peters J, Knight B, Hyde C, Ellard S, Pearson ER, et al (2017). Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in young-onset patients.
Diabetes Care,
40(8), 1017-1025.
Abstract:
Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in young-onset patients
OBJECTIVE Monogenic diabetes, a young-onset formof diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 fromnon-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. RESEARCH DESIGN AND METHODS We studied patients diagnosed at age 30 years or younger, currently younger than 50 years, in two U.K. regionswith existing high detection ofmonogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was 0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. RESULTS a total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8with cystic fibrosis-related diabetes).A total of 386 out of 1,365 (28%) patients had a UCPCR 0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases ofmonogenic diabeteswere diagnosed (8 commonMaturityOnset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95% CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. CONCLUSIONS the biomarker screening pathway formonogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. Theminimumprevalence ofmonogenic diabetes is 3.6%of patients diagnosed at age 30 years or younger.
Abstract.
Shields B, Colclough K (2017). Towards a systematic nationwide screening strategy for MODY.
Diabetologia,
60(4), 609-612.
Abstract:
Towards a systematic nationwide screening strategy for MODY
MODY is an early-onset monogenic form of diabetes. Correctly identifying MODY is of considerable importance as diagnosing the specific genetic subtype can inform the optimal treatment, with many patients being able to discontinue unnecessary insulin treatment. Diagnostic molecular genetic testing to confirm MODY is expensive, so screening strategies are required to identify the most appropriate patients for testing. In this issue of Diabetologia, Johansson and colleagues (DOI 10.1007/s00125-016-4167-1) describe a nationwide systematic screening approach to identify individuals with MODY in the paediatric age range. They focused testing on patients negative for both GAD and islet antigen 2 (IA-2) islet autoantibodies, thereby ruling out those with markers of type 1 diabetes, the most common form of diabetes in this age group. This commentary discusses the advantages and limitations of the approach, and the caution required when interpreting variants of uncertain pathogenicity identified from testing whole populations rather than targeting only patients with a strong MODY phenotype.
Abstract.
Bodea CA, Neale BM, Ripke S, Barclay M, Peyrin-Biroulet L, Chamaillard M, Colombel JF, Cottone M, Croft A, D'Incà R, et al (2016). A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies.
American Journal of Human Genetics,
98(5), 857-868.
Abstract:
A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies
One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.
Abstract.
Oram RA, Patel K, Hill A, Shields B, McDonald TJ, Jones A, Hattersley AT, Weedon MN (2016). A Type 1 Diabetes Genetic Risk Score can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults.
Diabetes Care,
39(3), 337-344.
Abstract:
A Type 1 Diabetes Genetic Risk Score can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults.
OBJECTIVE: with rising obesity, it is becoming increasingly difficult to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D) in young adults. There has been substantial recent progress in identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also to predict severe insulin deficiency in young adults with diabetes. RESEARCH DESIGN AND METHODS: We developed genetic risk scores (GRSs) from published T1D- and T2D-associated variants. We first tested whether the scores could distinguish clinically defined T1D and T2D from the Wellcome Trust Case Control Consortium (WTCCC) (n = 3,887). We then assessed whether the T1D GRS correctly classified young adults (diagnosed at 20-40 years of age, the age-group with the most diagnostic difficulty in clinical practice; n = 223) who progressed to severe insulin deficiency 0.280 (>50th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D GRS (
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Author URL.
Farmer AJ, Rodgers LR, Lonergan M, Shields B, Weedon MN, Donnelly L, Holman RR, Pearson ER, Hattersley AT (2016). Adherence to Oral Glucose-Lowering Therapies and Associations with 1-Year HbA1c: a Retrospective Cohort Analysis in a Large Primary Care Database.
Diabetes Care,
39(2), 258-263.
Abstract:
Adherence to Oral Glucose-Lowering Therapies and Associations with 1-Year HbA1c: a Retrospective Cohort Analysis in a Large Primary Care Database.
OBJECTIVE: the impact of taking oral glucose-lowering medicines intermittently, rather than as recommended, is unclear. We conducted a retrospective cohort study using community-acquired U.K. clinical data (Clinical Practice Research Database [CPRD] and GoDARTS database) to examine the prevalence of nonadherence to treatment for type 2 diabetes and investigate its potential impact on HbA1c reduction stratified by type of glucose-lowering medication. RESEARCH DESIGN AND METHODS: Data were extracted for patients treated between 2004 and 2014 who were newly prescribed metformin, sulfonylurea, thiazolidinedione, or dipeptidyl peptidase 4 inhibitors and who continued to obtain prescriptions over 1 year. Cohorts were defined by prescribed medication type, and good adherence was defined as a medication possession ratio ≥0.8. Linear regression was used to determine potential associations between adherence and 1-year baseline-adjusted HbA1c reduction. RESULTS: in CPRD and GoDARTS, 13% and 15% of patients, respectively, were nonadherent. Proportions of nonadherent patients varied by the oral glucose-lowering treatment prescribed (range 8.6% [thiazolidinedione] to 18.8% [metformin]). Nonadherent, compared with adherent, patients had a smaller HbA1c reduction (0.4% [4.4 mmol/mol] and 0.46% [5.0 mmol/mol] for CPRD and GoDARTs, respectively). Difference in HbA1c response for adherent compared with nonadherent patients varied by drug (range 0.38% [4.1 mmol/mol] to 0.75% [8.2 mmol/mol] lower in adherent group). Decreasing levels of adherence were consistently associated with a smaller reduction in HbA1c. CONCLUSIONS: Reduced medication adherence for commonly used glucose-lowering therapies among patients persisting with treatment is associated with smaller HbA1c reductions compared with those taking treatment as recommended. Differences observed in HbA1c responses to glucose-lowering treatments may be explained in part by their intermittent use.
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Jones AG, McDonald TJ, Shields BM, Hill AV, Hyde CJ, Knight BA, Hattersley AT (2016). Markers of β-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes.
Diabetes Care,
39(2), 250-257.
Abstract:
Markers of β-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes
Objective to assess whether clinical characteristics and simple biomarkers of β-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes. Research Design and Methods We prospectively studied 620 participants with type 2 diabetes and HbA1c ≥58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with β-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change. Results Reduced glycemic response to GLP-1RAs was associated with longer duration of diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine Cpeptide- to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P ≤ 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide ≤0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change 25.2 vs. 215.2 mmol/mol [20.5 vs. 21.4%], P = 0.005; C-peptide
Abstract.
Knight BA, Shields BM, Hattersley AT, Vaidya B (2016). Maternal hypothyroxinaemia in pregnancy is associated with obesity and adverse maternal metabolic parameters.
EUROPEAN JOURNAL OF ENDOCRINOLOGY,
174(1), 51-57.
Author URL.
Knight BA, Shields BM, Sturley R, Vaidya B (2016). Maternal thyroid function in pregnant women with a breech presentation in late gestation. Clinical Endocrinology, 85(2), 320-322.
Hope SV, Wienand-Barnett S, Shepherd M, King SM, Fox C, Khunti K, Oram RA, Knight BA, Hattersley AT, Jones AG, et al (2016). Practical Classification Guidelines for Diabetes in patients treated with insulin: a cross-sectional study of the accuracy of diabetes diagnosis.
The British journal of general practice : the journal of the Royal College of General Practitioners,
66(646), e315-e322.
Abstract:
Practical Classification Guidelines for Diabetes in patients treated with insulin: a cross-sectional study of the accuracy of diabetes diagnosis.
BackgroundDifferentiating between type 1 and type 2 diabetes is fundamental to ensuring appropriate management of patients, but can be challenging, especially when treating with insulin. The 2010 UK Practical Classification Guidelines for Diabetes were developed to help make the differentiation.AimTo assess diagnostic accuracy of the UK guidelines against 'gold standard' definitions of type 1 and type 2 diabetes based on measured C-peptide levels.Design and settingIn total, 601 adults with insulin-treated diabetes and diabetes duration ≥5 years were recruited in Devon, Northamptonshire, and Leicestershire.MethodBaseline information and home urine sample were collected. Urinary C-peptide creatinine ratio (UCPCR) measures endogenous insulin production. Gold standard type 1 diabetes was defined as continuous insulin treatment within 3 years of diagnosis and absolute insulin deficiency (UCPCR
Abstract.
Besser REJ, Flanagan SE, Mackay DGJ, Temple IK, Shepherd MH, Shields BM, Ellard S, Hattersley AT (2016). Prematurity and genetic testing for neonatal diabetes.
Pediatrics,
138(3).
Abstract:
Prematurity and genetic testing for neonatal diabetes
BACKGROUND: Hyperglycemia in premature infants is usually thought to reflect inadequate pancreatic development rather than monogenic neonatal diabetes. No studies, to our knowledge, have investigated the prevalence of monogenic forms of diabetes in preterm infants. METHODS: We studied 750 patients with diabetes diagnosed before 6 months of age. We compared the genetic etiology and clinical characteristics of 146 preterm patients born 32 weeks). Prematurity should not prevent referral for genetic testing as 37% have a potassium channel mutation and as a result can get improved control by replacing insulin with sulphonylurea therapy.
Abstract.
Hope SV, Knight BA, Shields BM, Hattersley AT, McDonald TJ, Jones AG (2016). Random non-fasting C–peptide: bringing robust assessment of endogenous insulin secretion to the clinic.
Diabetic Medicine,
33(11), 1554-1558.
Abstract:
Random non-fasting C–peptide: bringing robust assessment of endogenous insulin secretion to the clinic
Background: Measuring endogenous insulin secretion using C–peptide can assist diabetes management, but standard stimulation tests are impractical for clinical use. Random non-fasting C–peptide assessment would allow testing when a patient is seen in clinic. Methods: We compared C–peptide at 90 min in the mixed meal tolerance test (sCP) with random non-fasting blood C–peptide (rCP) and random non-fasting urine C–peptide creatinine ratio (rUCPCR) in 41 participants with insulin-treated diabetes [median age 72 (interquartile range 68–78); diabetes duration 21 (14–31) years]. We assessed sensitivity and specificity for previously reported optimal mixed meal test thresholds for severe insulin deficiency (sCP < 200 pmol//l) and Type 1 diabetes/inability to withdraw insulin (< 600 pmol//l), and assessed the impact of concurrent glucose. Results: rCP and sCP levels were similar (median 546 and 487 pmol//l, P = 0.92). rCP was highly correlated with sCP, r = 0.91, P < 0.0001, improving to r = 0.96 when excluding samples with concurrent glucose < 8 mmol//l. An rCP cut-off of 200 pmol//l gave 100% sensitivity and 93% specificity for detecting severe insulin deficiency, with area under the receiver operating characteristic curve of 0.99. rCP < 600 pmol//l gave 87% sensitivity and 83% specificity to detect sCP < 600 pmol//l. Specificity improved to 100% when excluding samples with concurrent glucose < 8 mmol//l. rUCPCR (0.52 nmol/mmol) was also well-correlated with sCP, r = 0.82, P < 0.0001. A rUCPCR cut-off of < 0.2 nmol/ mmol gave sensitivity and specificity of 83% and 93% to detect severe insulin deficiency, with area under the receiver operating characteristic curve of 0.98. Conclusions: Random non-fasting C–peptide measures are strongly correlated with mixed meal C–peptide, and have high sensitivity and specificity for identifying clinically relevant thresholds. These tests allow assessment of C–peptide at the point patients are seen for clinical care.
Abstract.
Jones AG, Lonergan M, Henley WE, Pearson ER, Hattersley AT, Shields BM (2016). Should Studies of Diabetes Treatment Stratification Correct for Baseline HbA1c?.
PLoS One,
11(4).
Abstract:
Should Studies of Diabetes Treatment Stratification Correct for Baseline HbA1c?
AIMS: Baseline HbA1c is a major predictor of response to glucose lowering therapy and therefore a potential confounder in studies aiming to identify other predictors. However, baseline adjustment may introduce error if the association between baseline HbA1c and response is substantially due to measurement error and regression to the mean. We aimed to determine whether studies of predictors of response should adjust for baseline HbA1c. METHODS: We assessed the relationship between baseline HbA1c and glycaemic response in 257 participants treated with GLP-1R agonists and assessed whether it reflected measurement error and regression to the mean using duplicate 'pre-baseline' HbA1c measurements not included in the response variable. In this cohort and an additional 2659 participants treated with sulfonylureas we assessed the relationship between covariates associated with baseline HbA1c and treatment response with and without baseline adjustment, and with a bias correction using pre-baseline HbA1c to adjust for the effects of error in baseline HbA1c. RESULTS: Baseline HbA1c was a major predictor of response (R2 = 0.19,β = -0.44,p
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Misra S, Shields B, Colclough K, Johnston DG, Oliver NS, Ellard S, Hattersley AT (2016). South Asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white European people. Diabetologia, 59(10), 2262-2265.
Shepherd M, Shields B, Hammersley S, Hudson M, McDonald TJ, Colclough K, Oram RA, Knight B, Hyde C, Cox J, et al (2016). Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatricdiabetes population with monogenic diabetes.
Diabetes Care,
39(11), 1879-1888.
Abstract:
Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatricdiabetes population with monogenic diabetes
OBJECTIVE Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing. RESEARCH DESIGN AND METHODS We studied 808 patients (79.5% of the eligible population)
Abstract.
Clissold R, Shields B, Ellard S, Hattersley A, Bingham C (2015). Assessment of the HNF1B Score as a Tool to Select Patients for HNF1B Genetic Testing.
Nephron,
130(2), 134-140.
Abstract:
Assessment of the HNF1B Score as a Tool to Select Patients for HNF1B Genetic Testing.
BACKGROUND/AIMS: Diagnosing hepatocyte nuclear factor 1β (HNF1B)-related disease is a challenging task due to the phenotypic variability and frequent absence of a family history. An HNF1B score has recently been developed to help select appropriate patients for genetic testing with a negative predictive value (NPV) of 99%. We aimed at testing the clinical utility of this score in a large number of referrals for HNF1B genetic testing to the UK diagnostic testing service for the HNF1B gene. METHODS: an HNF1B score was assigned for 686 UK referrals for HNF1B genetic testing using clinical information available at referral. The performance of the score was evaluated by receiver-operating characteristic curve analysis. The relative discriminatory ability of different clinical features for making a genetic diagnosis of HNF1B-related disease were estimated in the UK dataset alone and pooled with French data. RESULTS: the HNF1B score discriminated between patients with and without a mutation reasonably well with an area under the curve of 0.72. Applying the suggested cut-off score of ≥8 gave a NPV of 85%. In a pooled analysis, antenatal renal abnormalities, renal hyperechogenicity and cysts were discriminatory in children, whereas renal hypoplasia and cysts were discriminatory in adults. Pancreatic abnormalities were discriminatory in both, whereas other extra-renal characteristics had a large effect size only in adults. CONCLUSION: the HNF1B score was discriminatory for HNF1B mutations in a large cohort of individuals tested in a single UK centre. The lower NPV (85 vs. 99%) reduces its clinical utility in selecting patients for HNF1B genetic testing, although validation in a prospective cohort is required.
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Shields BM, Peters JL, Cooper C, Lowe J, Knight BA, Powell RJ, Jones A, Hyde CJ, Hattersley AT (2015). Can clinical features be used to differentiate type 1 from type 2 diabetes? a systematic review of the literature.
BMJ Open,
5(11).
Abstract:
Can clinical features be used to differentiate type 1 from type 2 diabetes? a systematic review of the literature.
OBJECTIVE: Clinicians predominantly use clinical features to differentiate type 1 from type 2 diabetes yet there are no evidence-based clinical criteria to aid classification of patients. Misclassification of diabetes is widespread (7-15% of cases), resulting in patients receiving inappropriate treatment. We sought to identify which clinical criteria could be used to discriminate type 1 and type 2 diabetes. DESIGN: Systematic review of all diagnostic accuracy studies published since 1979 using clinical criteria to predict insulin deficiency (measured by C-peptide). DATA SOURCES: 14 databases including: MEDLINE, MEDLINE in Process and EMBASE. The search strategy took the form of: (terms for diabetes) AND (terms for C-Peptide). ELIGIBILITY CRITERIA: Diagnostic accuracy studies of any routinely available clinical predictors against a reference standard of insulin deficiency defined by cut-offs of C-peptide concentrations. No restrictions on race, age, language or country of origin. RESULTS: 10,917 abstracts were screened, and 231 full texts reviewed. 11 studies met inclusion criteria, but varied by age, race, year and proportion of participants who were C-peptide negative. Age at diagnosis was the most discriminatory feature in 7/9 studies where it was assessed, with optimal cut-offs (>70% mean sensitivity and specificity) across studies being
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Knight BA, Shields BM, Brook A, Hill A, Bhat DS, Hattersley AT, Yajnik CS (2015). Lower Circulating B12 is Associated with Higher Obesity and Insulin Resistance during Pregnancy in a Non-Diabetic White British Population.
PLoS One,
10(8).
Abstract:
Lower Circulating B12 is Associated with Higher Obesity and Insulin Resistance during Pregnancy in a Non-Diabetic White British Population.
OBJECTIVE: Vitamin B12 and folate are critical micronutrients needed to support the increased metabolic demands of pregnancy. Recent studies from India have suggested that low vitamin B12 and folate concentrations in pregnancy are associated with increased obesity; however differences in diet, antenatal vitamin supplementation, and socioeconomic status may limit the generalisability of these findings. We aimed to explore the cross-sectional relationship of circulating serum vitamin B12 and folate at 28 weeks' gestation with maternal adiposity and related biochemical markers in a white non diabetic UK obstetric cohort. METHODS: Anthropometry and biochemistry data was available on 995 women recruited at 28 weeks gestation to the Exeter Family Study of Childhood Health. Associations between B12 and folate with maternal BMI and other obesity-related biochemical factors (HOMA-R, fasting glucose, triglycerides, HDL and AST) were explored using regression analysis, adjusting for potential confounders (socioeconomic status, vegetarian diet, vitamin supplementation, parity, haemodilution (haematocrit)). RESULTS: Higher 28 week BMI was associated with lower circulating vitamin B12 (r = -0.25; P
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Oram RA, McDonald TJ, Shields BM, Hudson MM, Shepherd MH, Hammersley S, Pearson ER, Hattersley AT, UNITED Team (2015). Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors.
Diabetes Care,
38(2), 323-328.
Abstract:
Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors.
OBJECTIVE: Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C-peptide levels in a large cross-sectional, population-based study of patients with T1D. RESEARCH DESIGN AND METHODS: We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay. RESULTS: Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR ≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling. CONCLUSIONS: This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment.
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Chakera AJ, Steele AM, Gloyn AL, Shepherd MH, Shields B, Ellard S, Hattersley AT (2015). Recognition and Management of Individuals with Hyperglycemia Because of a Heterozygous Glucokinase Mutation.
Diabetes Care,
38(7), 1383-1392.
Abstract:
Recognition and Management of Individuals with Hyperglycemia Because of a Heterozygous Glucokinase Mutation.
Glucokinase-maturity-onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. GCK gene mutations are present in ∼1 in 1,000 of the population, but most are not diagnosed. They are common causes of MODY (10-60%): persistent incidental childhood hyperglycemia (10-60%) and gestational diabetes mellitus (1-2%). GCK-MODY has a unique pathophysiology and clinical characteristics, so it is best considered as a discrete genetic subgroup. People with GCK-MODY have a defect in glucose sensing; hence, glucose homeostasis is maintained at a higher set point resulting in mild, asymptomatic fasting hyperglycemia (5.4-8.3 mmol/L, HbA1c range 5.8-7.6% [40-60 mmol/mol]), which is present from birth and shows slight deterioration with age. Even after 50 years of mild hyperglycemia, people with GCK-MODY do not develop significant microvascular complications, and the prevalence of macrovascular complications is probably similar to that in the general population. Treatment is not recommended outside pregnancy because glucose-lowering therapy is ineffective in people with GCK-MODY and there is a lack of long-term complications. In pregnancy, fetal growth is primarily determined by whether the fetus inherits the GCK gene mutation from their mother. Insulin treatment of the mother is only appropriate when increased fetal abdominal growth on scanning suggests the fetus is unaffected. The impact on outcome of maternal insulin treatment is limited owing to the difficulty in altering maternal glycemia in these patients. Making the diagnosis of GCK-MODY through genetic testing is essential to avoid unnecessary treatment and investigations, especially when patients are misdiagnosed with type 1 or type 2 diabetes.
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Stride A, Shields B, Gill-Carey O, Chakera AJ, Colclough K, Ellard S, Hattersley AT (2014). Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia.
Diabetologia,
57(1), 54-56.
Abstract:
Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia.
AIMS/HYPOTHESIS: Heterozygous glucokinase (GCK) mutations cause mild, fasting hyperglycaemia from birth. Although patients are usually asymptomatic and have glycaemia within target ranges, some are put on pharmacological treatment. We aimed to investigate how many patients are on pharmacological treatment and the impact of treatment on glycaemic control. METHODS: Treatment details were ascertained for 799 patients with heterozygous GCK mutations. In a separate, longitudinal study, HbA1c was obtained for 16 consecutive patients receiving insulin (n = 10) or oral hypoglycaemic agents (OHAs) (n = 6) whilst on treatment, and again having discontinued treatment following a genetic diagnosis of GCK-MODY. For comparison, HbA1c before and after genetic testing was studied in a control group (n = 18) not receiving pharmacological therapy. RESULTS: at referral for genetic testing, 168/799 (21%) of patients were on pharmacological treatment (13.5% OHAs, 7.5% insulin). There was no difference in the HbA1c of these patients compared with those receiving no treatment(median [IQR]: 48 [43, 51] vs 46 [43, 50] mmol/mol, respectively; 6.5% [6.1%, 6.8%] vs 6.4% [6.1%, 6.7%]; p = 0.11). Following discontinuation of pharmacological treatment in 16 patients, HbA1c did not change. The mean change in HbA1c was -0.68 mmol/mol (95% CI: -2.97, 1.61) (-0.06% [95% CI: -0.27, 0.15]). CONCLUSIONS/INTERPRETATION: Prior to a genetic diagnosis, 21% of patients were on pharmacological treatment. HbA1c was no higher than in untreated patients and did not change when therapy was discontinued, suggesting no impact on glycaemia. The lack of response to pharmacological therapy is likely to reflect the regulated hyperglycaemia seen in these patients owing to their glucose sensing defect and is an example of pharmacogenetics.
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Jones AG, McDonald TJ, Hattersley AT, Shields BM (2014). Effect of the holiday season in patients with diabetes: Glycemia and lipids increase postholiday, but the effect is small and transient. Diabetes Care, 37(5).
Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, Hattersley AT, McDonald TJ (2014). Erratum to: the majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells.
Diabetologia,
57(1).
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Sansbury FH, Cordell HJ, Bingham C, Bromilow G, Nicholls A, Powell R, Shields B, Smyth L, Warwicker P, Strain L, et al (2014). Factors determining penetrance in familial atypical haemolytic uraemic syndrome.
J Med Genet,
51(11), 756-764.
Abstract:
Factors determining penetrance in familial atypical haemolytic uraemic syndrome.
BACKGROUND: Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.3643C>G; p. Arg1215Gly) in whom a common lineage is probable. 25 individuals have been affected with aHUS with three peaks of incidence-early childhood (n=6), early adulthood (n=11) and late adulthood (n=8). Eighteen individuals who have not developed aHUS carry the mutation. METHODS: We estimated penetrance at the ages of 4, 27, 60 and 70 years as both a binary and a survival trait using MLINK and Mendel. We genotyped susceptibility factors in CFH, CD46 and CFHR1 in affected and unaffected carriers. RESULTS AND CONCLUSIONS: We found that the estimates of penetrance at the age of 4
years ranged from
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Medici M, Porcu E, Pistis G, Teumer A, Brown SJ, Jensen RA, Rawal R, Roef GL, Plantinga TS, Vermeulen SH, et al (2014). Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
PLoS Genet,
10(2).
Abstract:
Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P
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Jones AG, Shields BM, Hyde CJ, Henley WE, Hattersley AT (2014). Identifying good responders to glucose lowering therapy in type 2 diabetes: implications for stratified medicine.
PLoS One,
9(10).
Abstract:
Identifying good responders to glucose lowering therapy in type 2 diabetes: implications for stratified medicine.
AIMS: Defining responders to glucose lowering therapy can be important for both clinical care and for the development of a stratified approach to diabetes management. Response is commonly defined by either HbA1c change after treatment or whether a target HbA1c is achieved. We aimed to determine the extent to which the individuals identified as responders and non-responders to glucose lowering therapy, and their characteristics, depend on the response definition chosen. METHODS: We prospectively studied 230 participants commencing GLP-1 agonist therapy. We assessed participant characteristics at baseline and repeated HbA1c after 3 months treatment. We defined responders (best quartile of response) based on HbA1c change or HbA1c achieved. We assessed the extent to which these methods identified the same individuals and how this affected the baseline characteristics associated with treatment response. RESULTS: Different definitions of response identified different participants. Only 39% of responders by one definition were also good responders by the other. Characteristics associated with good response depend on the response definition chosen: good response by HbA1c achieved was associated with low baseline HbA1c (p
Abstract.
Author URL.
Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT (2014). Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
JAMA,
311(3), 279-286.
Abstract:
Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
IMPORTANCE: Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA1c) level that mimics recommended levels for type 1 and type 2 diabetes. OBJECTIVE: to assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with GCK mutations. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in the United Kingdom between August 2008 and December 2010. Assessment of microvascular and macrovascular complications in participants 35 years or older was conducted in 99 GCK mutation carriers (median age, 48.6 years), 91 nondiabetic, familial, nonmutation carriers (control) (median age, 52.2 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 54.7 years). MAIN OUTCOMES AND MEASURES: Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease. RESULTS: Median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with GCK had a low prevalence of clinically significant microvascular complications (1% [95% CI, 0%-5%]) that was not significantly different from controls (2% [95% CI, 0.3%-8%], P=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%], P
Abstract.
Author URL.
Hamilton AJ, Bingham C, McDonald TJ, Cook PR, Caswell RC, Weedon MN, Oram RA, Shields BM, Shepherd M, Inward CD, et al (2014). The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.
J Med Genet,
51(3), 165-169.
Abstract:
The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.
BACKGROUND: Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. METHODS AND RESULTS: We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. CONCLUSIONS: the HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.
Abstract.
Author URL.
Oram RA, Jones AG, Besser REJ, Knight BA, Shields BM, Brown RJ, Hattersley AT, McDonald TJ (2014). The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells.
Diabetologia,
57(1), 187-191.
Abstract:
The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells
Aims/hypothesis: Classically, type 1 diabetes is thought to proceed to absolute insulin deficiency. Recently developed ultrasensitive assays capable of detecting C-peptide under 5 pmol/l now allow very low levels of C-peptide to be detected in patients with long-standing type 1 diabetes. It is not known whether this low-level endogenous insulin secretion responds to physiological stimuli. We aimed to assess how commonly low-level detectable C-peptide occurs in long-duration type 1 diabetes and whether it responds to a meal stimulus. Methods: We performed a mixed-meal tolerance test in 74 volunteers with long-duration (>5 years) type 1 diabetes, i.e. with age at diagnosis 16 (9-23) years (median [interquartile range]) and diabetes duration of 30 (19-41) years. We assessed fasting and stimulated serum C-peptide levels using an electrochemiluminescence assay (detection limit 3.3 pmol/l), and also the urinary C-peptide:creatinine ratio (UCPCR). Results: Post-stimulation serum C-peptide was detectable at very low levels (>3.3 pmol/l) in 54 of 74 (73%) patients. In all patients with detectable serum C-peptide, C-peptide either increased (n = 43, 80%) or stayed the same (n = 11) in response to a meal, with no indication of levels falling (p < 0.0001). With increasing disease duration, absolute C-peptide levels fell although the numbers with detectable C-peptide remained high (68%, i.e. 25 of 37 patients with >30 years duration). Similar results were obtained for UCPCR. Conclusions/interpretation: Most patients with long-duration type 1 diabetes continue to secrete very low levels of endogenous insulin, which increase after meals. This is consistent with the presence of a small number of still functional beta cells and implies that beta cells are either escaping immune attack or undergoing regeneration. © 2013 the Author(s).
Abstract.
Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, Bos SD, Deelen J, den Heijer M, Freathy RM, et al (2013). A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function.
PLoS Genetics,
9(2).
Abstract:
A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
Abstract.
Shields BM, Knight BA, Hill AV, Hattersley AT, Vaidya B (2013). Five-year follow-up for women with subclinical hypothyroidism in pregnancy.
J Clin Endocrinol Metab,
98(12), E1941-E1945.
Abstract:
Five-year follow-up for women with subclinical hypothyroidism in pregnancy.
CONTEXT: Increasing numbers of women are being treated with l-thyroxine in pregnancy for mild thyroid dysfunction because of its association with impaired neuropsychological development in their offspring and other adverse obstetric outcomes. However, there are limited data to indicate whether treatment should be continued outside of pregnancy. OBJECTIVES: We aimed to determine whether subclinical hypothyroidism and maternal hypothyroxinemia resolve postdelivery. DESIGN, SETTING, AND PARTICIPANTS: a total of 523 pregnant healthy women with no known thyroid disorders were recruited during routine antenatal care and provided blood samples at 28 weeks of pregnancy and at a mean of 4.9 years postpregnancy. MAIN OUTCOME MEASURES: TSH, free T₄, free T₃, and thyroid peroxidase antibody levels were measured in serum taken in pregnancy and at follow-up. RESULTS: Subclinical hypothyroidism in pregnancy (TSH >3 mIU/L) was present in 65 of 523 (12.4%) women. of these, 49 (75.4%) women had normal thyroid function postpregnancy; 16 of 65 (24.6%) had persistent high TSH (TSH >4.5 mIU/L postpregnancy) with 3 women receiving l-thyroxine treatment. A total of 44 of 523 (8.4%) women had isolated maternal hypothyroxinemia in pregnancy (free T₄ 4.5 mIU/L outside pregnancy. of the women with subclinical hypothyroidism in pregnancy with antibody measurements available, those with thyroid peroxidase antibodies in pregnancy were more likely to have persistently elevated TSH or be receiving l-thyroxine replacement after pregnancy (6 of 7 [86%] vs 10 of 57 [18%], P <. 001). CONCLUSIONS: the majority of cases of subclinical hypothyroidism in pregnancy are transient, so treatment with l-thyroxine in these patients should be reviewed because it may not be warranted after pregnancy.
Abstract.
Author URL.
Besser REJ, Shields BM, Hammersley SE, Colclough K, McDonald TJ, Gray Z, Heywood JJN, Barrett TG, Hattersley AT (2013). Home urine C-peptide creatinine ratio (UCPCR) testing can identify type 2 and MODY in pediatric diabetes.
Pediatr Diabetes,
14(3), 181-188.
Abstract:
Home urine C-peptide creatinine ratio (UCPCR) testing can identify type 2 and MODY in pediatric diabetes.
BACKGROUND: Making the correct diabetes diagnosis in children is crucial for lifelong management. Type 2 diabetes and maturity onset diabetes of the young (MODY) are seen in the pediatric setting, and can be difficult to discriminate from type 1 diabetes. Postprandial urinary C-peptide creatinine ratio (UCPCR) is a non-invasive measure of endogenous insulin secretion that has not been tested as a diagnostic tool in children or in patients with diabetes duration
Abstract.
Author URL.
Besser REJ, Shields BM, Casas R, Hattersley AT, Ludvigsson J (2013). Lessons from the mixed-meal tolerance test: use of 90-minute and fasting C-peptide in pediatric diabetes.
Diabetes Care,
36(2), 195-201.
Abstract:
Lessons from the mixed-meal tolerance test: use of 90-minute and fasting C-peptide in pediatric diabetes.
OBJECTIVE: Mixed-meal tolerance test (MMTT) area under the curve C-peptide (AUC CP) is the gold-standard measure of endogenous insulin secretion in type 1 diabetes but is intensive and invasive to perform. The 90-min MMTT-stimulated CP ≥0.2 nmol/L (90CP) is related to improved clinical outcomes, and CP ≥0.1 nmol/L is the equivalent fasting measure (FCP). We assessed whether 90CP or FCP are alternatives to a full MMTT. RESEARCH DESIGN AND METHODS: CP was measured during 1,334 MMTTs in 421 type 1 diabetes patients aged
Abstract.
Author URL.
Steele AM, Wensley KJ, Brewer E, Shields BM, Hattersley AT, McDonald TJ (2013). Preanalytical sample handling of venous blood: How to ensure your glucose measurement is accurate and reliable.
Practical Diabetes,
30(3), 128-131.
Abstract:
Preanalytical sample handling of venous blood: How to ensure your glucose measurement is accurate and reliable
Measurement of blood glucose is a standard biochemical test requiring optimum preanalytical sample handling. Glucose measured in plasma from tubes containing sodium fluoride is recommended but serum from serum-gel tubes may be used in research situations. To help inform best practice, we assessed glucose stability in plasma and serum samples subjected to different preanalytical conditions. Fasting samples were taken from 10 non-diabetic volunteers into fluoride/EDTA and serum-gel tubes. Whole blood samples were pipetted into aliquots, placed on crushed ice or left at room temperature. Aliquots were centrifuged at 0, 2, 12, 24, and 48 hours. When neither ice nor centrifuge were available, plasma glucose was stable for 48 hours (96% of baseline); serum glucose degraded to 8% of baseline. When centrifuged and left at room temperature, plasma glucose was stable for 48 hours (101% of baseline) but, by 24 hours, serum glucose had fallen (94% of baseline). The result of un-centrifuged plasma on ice was stable (96% of baseline) at 48 hours; serum glucose had dropped to 92% of baseline by 12 hours. Plasma glucose and serum glucose were constant for 48 hours when separated and placed on ice within 2 hours: plasma glucose 101% of baseline; serum glucose 100% of baseline. Separated serum resting on the serum plug fell to 94% of baseline by 12 hours at room temperature and to 92% of baseline by 48 hours on ice. Clinically, we recommend that glucose is measured on plasma taken from fluoride tubes. Analysis should be undertaken as soon as practicable. In the research setting, glucose can be measured on plasma or serum but samples must be centrifuged and chilled soon after venepuncture and analysed within 48 hours. Copyright © 2013 John Wiley & Sons.
Abstract.
Shields BM, Henley W, Besser REJ, Hattersley AT, Ludvigsson J (2013). Response to Comment on: Besser et al. Lessons from the Mixed-Meal Tolerance Test: Use of 90-Minute and Fasting C-Peptide in Pediatric Diabetes. Diabetes Care 2013;36:195-201.
DIABETES CARE,
36(12), E222-E222.
Author URL.
Chakera AJ, Carleton VL, Shields B, Ross GP, Hattersley AT (2013). Response to Comment on: Chakera et al. Antenatal diagnosis of fetal genotype determines if maternal hyperglycemia due to a glucokinase mutation requires treatment. Diabetes Care 2012;35:1832-1834.
Diabetes Care,
36(1).
Author URL.
Hope SV, Jones AG, Goodchild E, Shepherd M, Besser REJ, Shields B, Mcdonald T, Knight BA, Hattersley A (2013). Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes.
Diabetic Medicine,
30(11), 1342-1348.
Abstract:
Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes
Aims: to determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. Methods: We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. Results: a total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide 0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m2, P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. Conclusions: Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion. © 2013 the Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.
Abstract.
Hope SV, Jones AG, Goodchild E, Shepherd M, Besser REJ, Shields B, McDonald T, Knight BA, Hattersley A (2013). Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes.
Diabet Med,
30(11), 1342-1348.
Abstract:
Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes.
AIMS: to determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. METHODS: We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. RESULTS: a total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide 0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m(2) , P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. CONCLUSIONS: Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion.
Abstract.
Author URL.
Oram RA, Rawlingson A, Shields BM, Bingham C, Besser REJ, McDonald TJ, Knight BA, Hattersley AT (2013). Urine C-peptide creatinine ratio can be used to assess insulin resistance and insulin production in people without diabetes: an observational study.
BMJ Open,
3(12).
Abstract:
Urine C-peptide creatinine ratio can be used to assess insulin resistance and insulin production in people without diabetes: an observational study.
OBJECTIVES: the current assessment of insulin resistance (IR) in epidemiology studies relies on the blood measurement of C-peptide or insulin. A urine C-peptide creatinine ratio (UCPCR) can be posted from home unaided. It is validated against serum measures of the insulin in people with diabetes. We tested whether UCPCR could be a surrogate measure of IR by examining the correlation of UCPCR with serum insulin, C-peptide and HOMA2 (Homeostasis Model Assessment 2)-IR in participants without diabetes and with chronic kidney disease (CKD). DESIGN: Observational study. SETTING: Single-centre clinical research facility. PARTICIPANTS: 37 healthy volunteers and 30 patients with CKD (glomerular filtration rate 15-60) were recruited. PRIMARY AND SECONDARY ENDPOINTS: Serum insulin, C-peptide and glucose at fasting (0), 30, 60, 90 and 120 min were measured during an oral glucose tolerance test (OGTT). Second-void fasting UCPCR and 120 min post-OGTT UCPCR were collected. HOMA2-IR was calculated using fasting insulin and glucose. The associations between UCPCR and serum measures were assessed using Spearman's correlations. RESULTS: in healthy volunteers, fasting second-void UCPCR strongly correlated with serum insulin (rs=0.69, p
Abstract.
Author URL.
Steele AM, Wensley KJ, Ellard S, Murphy R, Shepherd M, Colclough K, Hattersley AT, Shields BM (2013). Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies.
PLoS One,
8(6).
Abstract:
Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies.
AIMS: HaemoglobinA1c (HbA1c) is recommended for diabetes diagnosis but fasting plasma glucose (FPG) has been useful for identifying patients with glucokinase (GCK) mutations which cause lifelong persistent fasting hyperglycaemia. We aimed to derive age-related HbA1c reference ranges for these patients to determine how well HbA1c can discriminate patients with a GCK mutation from unaffected family members and young-onset type 1 (T1D) and type 2 diabetes (T2D) and to investigate the proportion of GCK mutation carriers diagnosed with diabetes using HbA1c and/or FPG diagnostic criteria. METHODS: Individuals with inactivating GCK mutations (n = 129), familial controls (n = 100), T1D (n = 278) and T2D (n = 319) aged ≥18years were recruited. Receiver Operating Characteristic (ROC) analysis determined effectiveness of HbA1c and FPG to discriminate between groups. RESULTS: HbA1c reference ranges in subjects with GCK mutations were: 38-56 mmol/mol (5.6-7.3%) if aged ≤40years; 41-60 mmol/mol (5.9-7.6%) if >40years. All patients (123/123) with a GCK mutation were above the lower limit of the HbA1c age-appropriate reference ranges. 69% (31/99) of controls were below these lower limits. HbA1c was also effective in discriminating those with a GCK mutation from those with T1D/T2D. Using the upper limit of the age-appropriate reference ranges to discriminate those with a mutation from those with T1D/T2D correctly identified 97% of subjects with a mutation. The majority (438/597 (73%)) with other types of young-onset diabetes had an HbA1c above the upper limit of the age-appropriate GCK reference range. HbA1c ≥48 mmol/mol classified more people with GCK mutations as having diabetes than FPG ≥7 mmol/l (68% vs. 48%, p = 0.0009). CONCLUSIONS: Current HbA1c diagnostic criteria increase diabetes diagnosis in patients with a GCK mutation. We have derived age-related HbA1c reference ranges that can be used for discriminating hyperglycaemia likely to be caused by a GCK mutation and aid identification of probands and family members for genetic testing.
Abstract.
Author URL.
Palmer ND, McDonough CW, Hicks PJ, Roh BH, Wing MR, an SS, Hester JM, Cooke JN, Bostrom MA, Rudock ME, et al (2012). A genome-wide association search for type 2 diabetes genes in African Americans.
PLoS One,
7(1).
Abstract:
A genome-wide association search for type 2 diabetes genes in African Americans.
African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P
Abstract.
Author URL.
Jones AG, Besser REJ, Shields BM, McDonald TJ, Hope SV, Knight BA, Hattersley AT (2012). Assessment of endogenous insulin secretion in insulin treated diabetes predicts postprandial glucose and treatment response to prandial insulin.
BMC Endocrine Disorders,
12Abstract:
Assessment of endogenous insulin secretion in insulin treated diabetes predicts postprandial glucose and treatment response to prandial insulin
Background: in patients with both Type 1 and Type 2 diabetes endogenous insulin secretion falls with time which changes treatment requirements, however direct measurement of endogenous insulin secretion is rarely performed. We aimed to assess the impact of endogenous insulin secretion on postprandial glucose increase and the effectiveness of prandial exogenous insulin.Methods: We assessed endogenous insulin secretion in 102 participants with insulin treated diabetes (58 Type 1) following a standardised mixed meal without exogenous insulin. We tested the relationship between endogenous insulin secretion and post meal hyperglycaemia. In 80 participants treated with fast acting breakfast insulin we repeated the mixed meal with participants' usual insulin given and assessed the impact of endogenous insulin secretion on response to exogenous prandial insulin.Results: Post meal glucose increment (90 minute - fasting) was inversely correlated with endogenous insulin secretion (90 minute C-peptide) (Spearman's r = -0.70, p < 0.001). Similar doses of exogenous prandial insulin lowered glucose increment more when patients had less endogenous insulin; by 6.4(4.2-11.1) verses 1.2(0.03-2.88) mmol/L (p < 0.001) for patients in the lowest verses highest tertiles of endogenous insulin.Conclusions: in insulin treated patients the measurement of endogenous insulin secretion may help predict the degree of postprandial hyperglycaemia and the likely response to prandial insulin. © 2012 Jones et al.; licensee BioMed Central Ltd.
Abstract.
McDonald TJ, Perry MH, Peake RWA, Pullan NJ, O'Connor J, Shields BM, Knight BA, Hattersley AT (2012). EDTA improves stability of whole blood C-peptide and insulin to over 24 hours at room temperature.
PLoS One,
7(7).
Abstract:
EDTA improves stability of whole blood C-peptide and insulin to over 24 hours at room temperature.
INTRODUCTION: C-peptide and insulin measurements in blood provide useful information regarding endogenous insulin secretion. Conflicting evidence on sample stability and handling procedures continue to limit the widespread clinical use of these tests. We assessed the factors that altered the stability of insulin and C-peptide in blood. METHODS: We investigated the impact of preservative type, time to centrifugation, storage conditions and duration of storage on the stability of C-peptide and insulin on three different analytical platforms. RESULTS: C-peptide was stable for at least 24 hours at room temperature in both centrifuged and whole blood collected in K(+)-EDTA and serum gel tubes, with the exception of whole blood serum gel, which decreased to 78% of baseline at 24 hours, (p = 0.008). Insulin was stable at room temperature for 24 hours in both centrifuged and whole blood collected in K(+)-EDTA tubes. In contrast insulin levels decreased in serum gel tubes both centrifuged and whole blood (66% of baseline, p = 0.01 and 76% of baseline p = 0.01, by 24 hours respectively). C-peptide and insulin remained stable after 6 freeze-thaw cycles. CONCLUSIONS: the stability of C-peptide and insulin in whole blood K(+)-EDTA tubes negates the need to conform to strict sample handling procedures for these assays, greatly increasing their clinical utility.
Abstract.
Author URL.
Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, et al (2012). High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
Nat Genet,
44(12), 1336-1340.
Abstract:
High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
Abstract.
Author URL.
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, et al (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
NATURE,
491(7422), 119-124.
Author URL.
Shields BM, Peters JL, Cooper C, Powell RJ, Knight BA, Hyde C, Hattersley AT (2012). Identifying clinical criteria to predict Type 1 diabetes, as defined by absolute insulin deficiency: a systematic review protocol.
BMJ Open,
2(6).
Abstract:
Identifying clinical criteria to predict Type 1 diabetes, as defined by absolute insulin deficiency: a systematic review protocol.
INTRODUCTION: Management of a patient's diabetes is entirely dependent upon the type of diabetes they are deemed to have. Patients with Type 1 diabetes are insulin deficient so require multiple daily insulin injections, whereas patients with Type 2 diabetes still have some endogenous insulin production so insulin treatment is only required when diet and tablets do not establish good glycaemic control. Despite the importance of a correct diagnosis, classification of diabetes is based on aetiology and relies on clinical judgement. There are no clinical guidelines on how to determine whether a patient has Type 1 or Type 2 diabetes. We aim to systematically review the literature to derive evidence-based clinical criteria for the classification of the major subtypes of diabetes. METHODS AND ANALYSIS: We will perform a systematic review of diagnostic accuracy studies to establish clinical criteria that predict the subsequent development of absolute insulin deficiency seen in Type 1 diabetes. Insulin deficiency will be determined by reference standard C-peptide concentrations. Synthesis of criteria identified will be undertaken using hierarchical summary receiver operating characteristic curves. ETHICS AND DISSEMINATION: As this is a systematic review, there will be no ethical issues. We will disseminate results by writing up the final systematic review and synthesis for publication in a peer-reviewed journal and will present at national and international diabetes-related meetings.
Abstract.
Author URL.
McDonald TJ, McEneny J, Pearson ER, Thanabalasingham G, Szopa M, Shields BM, Ellard S, Owen KR, Malecki MT, Hattersley AT, et al (2012). Lipoprotein composition in HNF1A-MODY: Differentiating between HNF1A-MODY and Type 2 diabetes.
Clinica Chimica Acta,
413(9-10), 927-932.
Abstract:
Lipoprotein composition in HNF1A-MODY: Differentiating between HNF1A-MODY and Type 2 diabetes
Introduction: the young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia.We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. Methods: 1)14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups.2)HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. Results: 1)In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93mmol/l, p=0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15mmol/l, p=0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33mmol/L, p=0.04 and 1.10 vs. 0.83mmol/L, p=0.019, respectively), but were similar to controls (1.59 vs. 1.45mmol/L, p=0.35 and 1.10 vs. 1.21mmol/L, p=0.19, respectively).2)A plasma-HDL-cholesterol >1.12mmol/L was 75% sensitive and 64% specific (ROC AUC=0.76) at discriminating HNF1A-MODY from Type 2 diabetes. Conclusion: the plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. © 2012 Elsevier B.V.
Abstract.
McDonald TJ, McEneny J, Pearson ER, Thanabalasingham G, Szopa M, Shields BM, Ellard S, Owen KR, Malecki MT, Hattersley AT, et al (2012). Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
Clin Chim Acta,
413(9-10), 927-932.
Abstract:
Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
INTRODUCTION: the young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. METHODS: 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. RESULTS: 1) in HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) a plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. CONCLUSION: the plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.
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Cooper JD, Simmonds MJ, Walker NM, Burren O, Brand OJ, Guo H, Wallace C, Stevens H, Coleman G, Wellcome Trust Case Control Consortium, et al (2012). Seven newly identified loci for autoimmune thyroid disease.
Hum Mol Genet,
21(23), 5202-5208.
Abstract:
Seven newly identified loci for autoimmune thyroid disease.
Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.
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Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT (2012). The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes.
Diabetologia,
55(5), 1265-1272.
Abstract:
The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes.
AIMS/HYPOTHESIS: Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual's probability of having MODY, as a crucial tool for rational genetic testing. METHODS: We developed prediction models using logistic regression on data from 1,191 patients with MODY (n = 594), type 1 diabetes (n = 278) and type 2 diabetes (n = 319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. RESULTS: the models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA(1c), parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA(1c), parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic = 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic = 0.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis
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Thomas NJ, Shields BM, Besser REJ, Jones AG, Rawlingson A, Goodchild E, Leighton C, Bowman P, Shepherd M, Knight BA, et al (2012). The impact of gender on urine C-peptide creatinine ratio interpretation.
Ann Clin Biochem,
49(Pt 4), 363-368.
Abstract:
The impact of gender on urine C-peptide creatinine ratio interpretation.
BACKGROUND: Urinary C-peptide creatinine ratio (UCPCR) is a non-invasive and convenient way of assessing endogenous insulin production. Adjusting for urine creatinine levels allows for differences in urine concentration. Creatinine excretion is known to be higher in men due to gender differences in muscle mass. We investigated the impact of gender on UCPCR. METHODS: One hundred and seventy-six subjects underwent a mixed meal tolerance test (MMTT). We looked at the relationship between UCPCR on urine C-peptide and creatinine excretion rates using timed post-meal urine samples. A further 415 subjects had two-hour post-meal UCPCR measurements in order to derive gender-specific percentiles for different diabetes subgroups and controls. RESULTS: UCPCR was 1.48-fold higher in women (n=78) than men (n=98), median (interquartile range [IQR]): 1.88 (0.49-3.49) men versus 2.88 (1.58-4.91) nmol mmol(-1) women, P=0.01. This reflects a gender difference in creatinine excretion rates (11.5 [8.3-13.7] men versus 8.2 [5.6-9.1] women μmol min(-1) P
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Besser REJ, Jones AG, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2012). The impact of insulin administration during the mixed meal tolerance test.
Diabet Med,
29(10), 1279-1284.
Abstract:
The impact of insulin administration during the mixed meal tolerance test.
AIMS: the mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test. METHODS: Ninety-one adults with insulin-treated diabetes (Type 1 n = 56, Type 2 n = 35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin. RESULTS: the 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin (r = 0.98, P < 0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P = 0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (≥ 0.2 nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C-peptide was highly correlated to 90-min serum C-peptide during the test (r = 0.97, P < 0.0001). A fasting serum C-peptide ≥ 0.07 nmol/l was the optimal cut-off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide ≥ 0.2 nmol/l). CONCLUSIONS: Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients.
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Bowman P, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2012). Validation of a single-sample urinary C-peptide creatinine ratio as a reproducible alternative to serum C-peptide in patients with Type 2 diabetes.
Diabet Med,
29(1), 90-93.
Abstract:
Validation of a single-sample urinary C-peptide creatinine ratio as a reproducible alternative to serum C-peptide in patients with Type 2 diabetes.
AIMS: Serum C-peptide can be used in Type 2 diabetes as a measure of endogenous insulin secretion, but practicalities of collection limit its routine clinical use. Urine C-peptide creatinine ratio is a non-invasive alternative that is stable for at least 3 days at room temperature in boric acid preservative. We aimed to assess the utility of urine C-peptide creatinine ratio in individuals with Type 2 diabetes as an alternative to serum C-peptide. METHODS: We assessed, in 77 individuals with Type 2 diabetes, the reproducibility of, and correlations between, fasting and postprandial urine C-peptide creatinine ratio and serum C-peptide, and the impact of renal impairment (estimated glomerular filtration rate < 60 ml min(-1) 1.73 m(-2)) on these correlations. RESULTS: Urine C-peptide creatinine ratio was at least as reproducible as serum C-peptide [fasting coefficient of variation mean (95% CI): 28 (21-35)% vs. 38 (26-59)% and 2-h post-meal 26 (18-33)% vs. 27 (20-34)%. Urine C-peptide creatinine ratio 2 h post-meal was correlated with stimulated serum C-peptide, both the 2-h value (r = 0.64, P < 0.001) and the 2-h area under the C-peptide curve (r = 0.63, P < 0.001). The association seen was similar in patients with and without moderate renal impairment (P = 0.6). CONCLUSIONS: in patients with Type 2 diabetes, a single urine C-peptide creatinine ratio is a stable, reproducible measure that is well correlated with serum C-peptide following meal stimulation, even if there is moderate renal impairment. Urine C-peptide creatinine ratio therefore has potential for use in clinical practice in the assessment of Type 2 diabetes.
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Taylor PN, Panicker V, Sayers A, Shields B, Iqbal A, Bremner AP, Beilby JP, Leedman PJ, Hattersley AT, Vaidya B, et al (2011). A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.
Eur J Endocrinol,
164(5), 773-780.
Abstract:
A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.
OBJECTIVE: Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T(4)). DESIGN: Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T(4)). METHODS: Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T(3)), and T(4) levels. RESULTS: Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64 × 10(-10) 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T(4) (P=0.023, -0.07 s.d./allele, 95% CI -0.137, -0.01), no association was seen with free T(3) (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T(4) in 1981 (-0.068 s.d./allele, 95% CI -0.167, 0.031) and 1994 (-0.07 s.d./allele, 95% CI -0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T(4). CONCLUSION: Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T(4) levels that are consistent over time and lost in individuals on l-T(4). These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.
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Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, et al (2011). Erratum: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genetics, 43(4).
Shields BM, Knight BA, Hill A, Hattersley AT, Vaidya B (2011). Fetal thyroid hormone level at birth is associated with fetal growth.
J Clin Endocrinol Metab,
96(6), E934-E938.
Abstract:
Fetal thyroid hormone level at birth is associated with fetal growth.
CONTEXT: Thyroid function is known to play an important role in fetal neurological development, but its role in regulating fetal growth is not well established. Overt maternal and fetal thyroid disorders are associated with reduced birth weight. We hypothesized that, even in the absence of overt thyroid dysfunction, maternal and fetal thyroid function influence fetal growth. AIM: in normal, healthy pregnancies, we aimed to assess whether fetal thyroid hormone at birth (as measured in cord blood) is associated with fetal growth. We also aimed to study whether fetal thyroid hormone at birth is associated with maternal thyroid hormone in the third trimester. METHODS: in 616 healthy mother-child pairs, TSH, free T(4) (FT4), and free T(3) (FT3) were measured in mothers at 28 wk gestation and in umbilical cord blood at birth. Birth weight, length, head circumference, and tricep and bicep skinfold thicknesses were measured on the babies. RESULTS: Cord FT4 was associated with birth weight (r = 0.25; P < 0.001), length (r = 0.17; P < 0.001), and sum of skinfolds (r = 0.19; P < 0.001). There were no associations between birth measurements and either cord TSH or cord FT3. Maternal FT4 and cord FT4 were correlated (r = 0.14; P = 0.0004), and there were weaker negative associations between maternal TSH and cord FT4 (r = -0.08; P = 0.04) and FT3 (r = -0.10; P = 0.01). CONCLUSION: Associations between cord FT4 and birth size suggest that fetal thyroid function may be important in regulating fetal growth, both of skeletal size and fat. The correlation between third-trimester maternal FT4 and cord FT4 supports the belief that maternal T(4) crosses the placenta even in late gestation.
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Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, et al (2011). Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits. PLoS Genetics, 7(3), e1001324-e1001324.
Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE, et al (2011). Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature Genetics, 43(11), 1131-1138.
McDonald TJ, Shields BM, Lawry J, Owen KR, Gloyn AL, Ellard S, Hattersley AT (2011). High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes.
Diabetes Care,
34(8), 1860-1862.
Abstract:
High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes.
OBJECTIVE: Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS: hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-α [HNF4A], 21 HNF1-β (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS: hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1-0.6] mg/L) than type 2 diabetes (1.40 [0.60-3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50-1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46-2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30-1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10-2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP
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McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P, Williams A, Hattersley AT, Ellard S (2011). Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.
Diabet Med,
28(9), 1028-1033.
Abstract:
Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.
AIM: Maturity-onset diabetes of the young is a monogenic form of familial, young-onset diabetes. It is rare (∼1% diabetes) and may be misdiagnosed as Type 1 diabetes and inappropriately treated with insulin. Type 1 diabetes is characterized by the presence of islet autoantibodies, including glutamate decarboxylase (GAD) and islet antigen-2 (IA-2) antibodies. The prevalence of islet autoantibodies is unknown in maturity-onset diabetes of the young and may have the potential to differentiate this form of diabetes from Type 1 diabetes. The aim of this study was to determine the prevalence of GAD and IA-2 antibodies in patients with maturity-onset diabetes of the young and Type 1 diabetes. METHODS: We measured plasma GAD and IA-2 antibodies in 508 patients with the most common forms of maturity-onset diabetes of the young (GCK: n = 227; HNF1A: n = 229; HNF4A: n = 52) and 98 patients with newly diagnosed Type 1 diabetes (diagnosed < 6 months). Autoantibodies were considered positive if ≥ 99th centile of 500 adult control subjects. RESULTS: GAD and/or IA-2 antibodies were present in 80/98 (82%) patients with Type 1 diabetes and 5/508 (< 1%) patients with maturity-onset diabetes of the young. In the cohort with Type 1 diabetes, both GAD and IA-2 antibodies were detected in 37.8% of patients, GAD only in 24.5% and IA-2 only in 19.4%. All five patients with maturity-onset diabetes of the young with detectable antibodies had GAD antibodies and none had detectable IA-2 antibodies. CONCLUSION: the prevalence of GAD and IA-2 antibodies in maturity-onset diabetes of the young is the same as in control subjects (< 1%). The finding of islet autoantibodies, especially IA-2 antibodies, makes the diagnosis of maturity-onset diabetes of the young very unlikely and genetic testing should only be performed if other clinical characteristics strongly suggest this form of diabetes rather than Type 1 diabetes. This supports routine islet autoantibody testing before proceeding to more expensive molecular genetic testing.
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De Silva NMG, Freathy RM, Palmer TM, Donnelly LA, Luan J, Gaunt T, Langenberg C, Weedon MN, Shields B, Knight BA, et al (2011). Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.
Diabetes,
60(3), 1008-1018.
Abstract:
Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.
OBJECTIVE: the causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS: We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS: Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). CONCLUSIONS: Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
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Kilpeläinen TO, Den Hoed M, Ong KK, Grøntved A, Brage S, Jameson K, Cooper C, Khaw KT, Ekelund U, Wareham NJ, et al (2011). Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals.
American Journal of Clinical Nutrition,
93(4), 851-860.
Abstract:
Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals
Background: High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. Objective: the objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. Design: a meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (nmax = 14,060); 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (nmax = 10,623); and 3) all published data (nmax = 14,837). Results: Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (β ± SE: -13 ± 5 g/allele; P = 0.012; n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (β ± SE: 11 ± 4 g/allele; P = 0.013; n = 28,219). These results were not significant after correction for multiple testing. Conclusions: Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity. © 2011 American Society for Nutrition.
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Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Knight BA, Ellard S, Hattersley AT (2011). Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-{alpha}/hepatocyte nuclear factor 4-{alpha} maturity-onset diabetes of the young from long-duration type 1 diabetes.
Diabetes Care,
34(2), 286-291.
Abstract:
Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-{alpha}/hepatocyte nuclear factor 4-{alpha} maturity-onset diabetes of the young from long-duration type 1 diabetes.
OBJECTIVE: Hepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with diabetes for ≥ 5 years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes. RESULTS: UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (
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Besser REJ, Ludvigsson J, Jones AG, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2011). Urine C-peptide creatinine ratio is a noninvasive alternative to the mixed-meal tolerance test in children and adults with type 1 diabetes.
Diabetes Care,
34(3), 607-609.
Abstract:
Urine C-peptide creatinine ratio is a noninvasive alternative to the mixed-meal tolerance test in children and adults with type 1 diabetes.
OBJECTIVE: Stimulated serum C-peptide (sCP) during a mixed-meal tolerance test (MMTT) is the gold standard measure of endogenous insulin secretion, but practical issues limit its use. We assessed urine C-peptide creatinine ratio (UCPCR) as an alternative. RESEARCH DESIGN AND METHODS: Seventy-two type 1 diabetic patients (age of diagnosis median 14 years [interquartile range 10-22]; diabetes duration 6.5 [2.3-32.7]) had an MMTT. sCP was collected at 90 min. Urine for UCPCR was collected at 120 min and following a home evening meal. RESULTS: MMTT 120-min UCPCR was highly correlated to 90-min sCP (r = 0.97; P < 0.0001). UCPCR ≥ 0.53 nmol/mmol had 94% sensitivity/100% specificity for significant endogenous insulin secretion (90-min sCP ≥ 0.2 nmol/L). The 120-min postprandial evening meal UCPCR was highly correlated to 90-min sCP (r = 0.91; P < 0.0001). UCPCR ≥ 0.37 nmol/mmol had 84% sensitivity/97% specificity for sCP ≥ 0.2 nmol/L. CONCLUSIONS: UCPCR testing is a sensitive and specific method for detecting insulin secretion. UCPCR may be a practical alternative to serum C-peptide testing, avoiding the need for inpatient investigation.
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Jones AG, Besser REJ, McDonald TJ, Shields BM, Hope SV, Bowman P, Oram RA, Knight BA, Hattersley AT (2011). Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes.
Diabet Med,
28(9), 1034-1038.
Abstract:
Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes.
AIMS: Serum C-peptide measurement can assist clinical management of diabetes, but practicalities of collection limit widespread use. Urine C-peptide creatinine ratio may be a non-invasive practical alternative. The stability of C-peptide in urine allows outpatient or community testing. We aimed to assess how urine C-peptide creatinine ratio compared with serum C-peptide measurement during a mixed-meal tolerance test in individuals with late-onset, insulin-treated diabetes. METHODS: We correlated the gold standard of a stimulated serum C-peptide in a mixed-meal tolerance test with fasting and stimulated (mixed-meal tolerance test, standard home meal and largest home meal) urine C-peptide creatinine ratio in 51 subjects with insulin-treated diabetes (diagnosis after age 30 years, median age 66 years, median age at diagnosis 54, 42 with Type 2 diabetes, estimated glomerular filtration rate > 60 ml min(-1) 1.73 m(-2) ). RESULTS: Ninety-minute mixed-meal tolerance test serum C-peptide is correlated with mixed-meal tolerance test-stimulated urine C-peptide creatinine ratio (r = 0.82), urine C-peptide creatinine ratio after a standard breakfast at home (r = 0.73) and urine C-peptide creatinine ratio after largest home meal (r = 0.71). A stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.3 nmol/mmol had a 100% sensitivity and 96% specificity (area under receiver operating characteristic curve = 0.99) in identifying subjects without clinically significant endogenous insulin secretion (mixed-meal tolerance test-stimulated C-peptide < 0.2 nmol/l). In detecting a proposed serum C-peptide threshold for insulin requirement (stimulated serum C-peptide < 0.6 nmol/l), a stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.6 nmol/mmol had a sensitivity and specificity of 92%. CONCLUSION: in patients with insulin-treated diabetes diagnosed after age 30 years, urine C-peptide creatinine ratio is well correlated with serum C-peptide and may provide a practical alternative measure to detect insulin deficiency for use in routine clinical practice.
Abstract.
Author URL.
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, et al (2010). Erratum: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk (Nature Genetics (2010) 42 (105-116)). Nature Genetics, 42(5).
Perry JRB, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, Sparsø T, Thorleifsson G, Grallert H, Ferrucci L, Maggio M, et al (2010). Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.
Hum Mol Genet,
19(3), 535-544.
Abstract:
Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the a allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
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Author URL.
Shields BM, Freathy RM, Hattersley AT (2010). Genetic influences on the association between fetal growth and susceptibility to type 2 diabetes.
JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE,
1(2), 96-105.
Author URL.
Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF, et al (2010). Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
Nature,
464(7289), 713-720.
Abstract:
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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Author URL.
Steele AM, Shields BM, Shepherd M, Ellard S, Hattersley AT, Pearson ER (2010). Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene.
Diabet Med,
27(2), 157-161.
Abstract:
Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene.
AIMS: to investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1alpha gene (HNF1A). METHODS: We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics. RESULTS: Data were collated on 241 control subjects and 153 mutation carriers. of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects (P = 0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P = 0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P = 0.006)]. CONCLUSIONS: We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile.
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Veeramootoo D, Shore AC, Shields B, Krishnadas R, Cooper M, Berrisford RG, Wajed SA (2010). Ischemic conditioning shows a time-dependant influence on the fate of the gastric conduit after minimally invasive esophagectomy.
Surg Endosc,
24(5), 1126-1131.
Abstract:
Ischemic conditioning shows a time-dependant influence on the fate of the gastric conduit after minimally invasive esophagectomy.
BACKGROUND: Minimally invasive esophagectomy (MIO) is now established as a valid alternative to open surgery for the management of esophagogastric cancers. However, a high incidence of ischemia-related gastric conduit failure (ICF) is observed, which is detrimental to any potential benefits of this approach. METHODS: Since April 2004, MIO has been the procedure of choice for esophagogastric resection in the authors' unit. Data relating to the surgical technique were collected, with a focus on ischemic conditioning by laparoscopic ligation of the left gastric artery (LIC) 2 weeks or 5 days before resection. RESULTS: a total of 97 patients underwent a planned MIO. Four in-patient deaths (4.1%) occurred, none of which were conduit related, and overall, 20 patients experienced ICF (20.6%). In four patients, ICF was recognized and dealt with at the initial surgery. The remaining 16 patients experienced this complication postoperatively, with 9 (9.3%) of them requiring further surgery. of the 97 patients, 55 did not undergo ischemic conditioning, and conduit failure was observed in 11 (20%). Thirty-five patients had LIC at 2 weeks, and 2 (5.7%) experienced ICF. All seven patients (100%) who had LIC at 5 days experienced ICF. Timing of ischemic conditioning (p < 0.0001) had a definite impact on the conduit failure rate, and the benefit of ischemic conditioning at 2 weeks compared with no conditioning neared significance (p = 0.07). CONCLUSIONS: Ischemic failure of the gastric conduit significantly impairs recovery after MIO. Ischemic conditioning 2 weeks before surgery may reduce this complication and allow the benefits of this approach to be realized.
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Author URL.
Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S (2010). Maturity-onset diabetes of the young (MODY): how many cases are we missing?.
Diabetologia,
53(12), 2504-2508.
Abstract:
Maturity-onset diabetes of the young (MODY): how many cases are we missing?
AIMS/HYPOTHESIS: Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence. METHODS: UK referrals for genetic testing in 2,072 probands and 1,280 relatives between 1996 and 2009 were examined by region, country and test result. Referral rate and prevalence were calculated using UK Census 2001 figures. RESULTS: MODY was confirmed in 1,177 (35%) patients, with HNF1A (52%) and GCK mutations (32%) being most frequent in probands confirmed with MODY. There was considerable regional variation in proband referral rates (from 50 per million for South West England and Scotland) and patients diagnosed with MODY (5.3 per million in Northern Ireland, 48.9 per million in South West England). Referral rates and confirmed cases were highly correlated (r = 0.96, p < 0.0001). The minimum prevalence of MODY was estimated to be 108 cases per million. CONCLUSIONS/INTERPRETATION: Assuming this minimal prevalence throughout the UK then >80% of MODY is not diagnosed by molecular testing. The marked regional variation in the prevalence of confirmed MODY directly results from differences in referral rates. This could reflect variation in awareness of MODY or unequal access to genetic testing. Increased referral for diagnostic testing is required if the majority of MODY patients are to have the genetic diagnosis necessary for optimal treatment.
Abstract.
Author URL.
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, et al (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Nat Genet,
42(2), 105-116.
Abstract:
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
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Author URL.
Lango Allen H, Johansson S, Ellard S, Shields B, Hertel JK, Raeder H, Colclough K, Molven A, Frayling TM, Njølstad PR, et al (2010). Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes.
Diabetes,
59(1), 266-271.
Abstract:
Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes.
OBJECTIVE: Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS: Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS: We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years if present, P = 1.6 x 10(-10)) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x 10(-2)). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x 10(-4)) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x 10(-38)). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x 10(-3)). CONCLUSIONS: We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants.
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Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, et al (2010). Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
Nature Genetics,
42(7), 579-589.
Abstract:
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. © 2010 Nature America, Inc. All rights reserved.
Abstract.
Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, Warrington NM, Widen E, Hottenga JJ, Kaakinen M, et al (2010). Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
Nat Genet,
42(5), 430-435.
Abstract:
Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.
Abstract.
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Freathy RM, Ring SM, Shields B, Galobardes B, Knight B, Weedon MN, Smith GD, Frayling TM, Hattersley AT (2009). A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy.
Hum Mol Genet,
18(15), 2922-2927.
Abstract:
A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy.
Maternal smoking during pregnancy is associated with low birth weight and adverse pregnancy outcomes. Women are more likely to quit smoking during pregnancy than at any other time in their lives, but some pregnant women continue to smoke. A recent genome-wide association study demonstrated an association between a common polymorphism (rs1051730) in the nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) and both smoking quantity and nicotine dependence. We aimed to test whether the same polymorphism that predisposes to greater cigarette consumption would also reduce the likelihood of smoking cessation in pregnancy. We studied 7845 pregnant women of European descent from the South-West of England. Using 2474 women who smoked regularly immediately pre-pregnancy, we analysed the association between the rs1051730 risk allele and both smoking cessation during pregnancy and smoking quantity. Each additional copy of the risk allele was associated with a 1.27-fold higher odds (95% CI 1.11-1.45) of continued smoking during pregnancy (P = 0.0006). Adjustment for pre-pregnancy smoking quantity weakened, but did not remove this association [odds ratio (OR) 1.20 (95% CI 1.03-1.39); P = 0.018]. The same risk allele was also associated with heavier smoking before pregnancy and in the first, but not the last, trimester [OR for smoking 10+ cigarettes/day versus 1-9/day in first trimester = 1.30 (95% CI 1.13-1.50); P = 0.0003]. To conclude, we have found strong evidence of association between the rs1051730 variant and an increased likelihood of continued smoking in pregnancy and have confirmed the previously observed association with smoking quantity. Our data support the role of genetic factors in influencing smoking cessation during pregnancy.
Abstract.
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Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT (2009). A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients.
Diabet Med,
26(4), 437-441.
Abstract:
A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients.
BACKGROUND AND AIMS: Hepatocyte nuclear factor-1 alpha (HNF1A) gene mutations are the commonest cause of monogenic diabetes, but patients are often misdiagnosed as having Type 1 diabetes and started on insulin treatment. Patients with HNF1A diabetes are particularly sensitive to the glucose-lowering effect of sulphonylureas, which are the pharmacological treatment of choice. We aimed to assess if patients do change from insulin to sulphonylurea treatment when HNF1A diabetes is confirmed and the impact of this treatment change on long-term glycaemic control. METHODS: We investigated the clinical course of 43 patients who were insulin treated from diagnosis for a median 4 years (range 1-14) before an HNF1A gene mutation was identified. RESULTS: Thirty-four patients (79%) stopped insulin following genetic testing and transferred to sulphonylureas. Twenty-four of them (71%) remained off insulin at a median 39 months (range 17-90) post-transfer. The 10 patients who recommenced insulin had a trend towards a longer duration of diabetes (18 vs. 7 years, P = 0.066) compared with those remaining on tablets. The median glycated haemoglobin (HbA(1c)) was good (6.9%; interquartile range 6.3-8.0%) in the patients who remained off insulin and 19/24 patients (79%) achieved HbA(1c) < 7.5% or improved their pre-genetic diagnosis HbA(1c) by > 1.0%. Transfer off insulin was not attempted in eight patients: one of these was planning pregnancy and two chose to remain on insulin. CONCLUSION: in this observational study we found that a molecular genetic diagnosis of HNF1A diabetes does alter treatment in clinical practice, with 79% attempting transfer to sulphonylureas. Transfer to sulphonylureas was successful in the majority of patients without deterioration in glycaemic control.
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Shields B, Hill A, Bilous M, Knight B, Hattersley AT, Bilous RW, Vaidya B (2009). Cigarette smoking during pregnancy is associated with alterations in maternal and fetal thyroid function.
J Clin Endocrinol Metab,
94(2), 570-574.
Abstract:
Cigarette smoking during pregnancy is associated with alterations in maternal and fetal thyroid function.
CONTEXT: Studies in the general population have shown lower serum TSH levels in smokers as compared with nonsmokers. AIM: Our aim was to examine whether smoking is associated with changes in thyroid function of pregnant women and their fetus. SUBJECTS AND METHODS: We examined the relationship between smoking and thyroid function (serum TSH, free T4, and free T3) in two independent cohorts of pregnant women without a history of thyroid disorder or an overt biochemical thyroid dysfunction: 1) first-trimester cohort (median gestation 9 wk) (n = 1428) and 2) third-trimester cohort (gestation 28 wk) (n = 927). We also analyzed the relationship between maternal smoking and thyroid hormone levels in cord serum of 618 full-term babies born to the women in the third-trimester cohort. RESULTS: in smokers compared with nonsmokers, median serum TSH was lower (first-trimester cohort: 1.02 vs. 1.17 mIU/liter, P = 0.001; third-trimester cohort: 1.72 vs. 1.90 mIU/liter, P = 0.037), and median serum FT3 was higher (first-trimester cohort: 5.1 vs. 4.9 pmol/liter, P < 0.0001; third-trimester cohort: 4.4 vs. 4.1 pmol/liter, P < 0.0001). In both cohorts, serum FT4 in smokers and nonsmokers were similar. The prevalence of anti-thyroperoxidase antibodies was also similar in smokers and nonsmokers in both cohorts. Cord serum TSH of babies born to smokers was lower than of those born to nonsmokers (6.7 vs. 8.1 mIU/liter, P = 0.009). CONCLUSIONS: Cigarette smoking is associated with changes in maternal thyroid function throughout the pregnancy and in fetal thyroid function as measured in cord blood samples.
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Shields BM, Freathy RM, Knight BA, Hill A, Weedon MN, Frayling TM, Hattersley AT, Vaidya B (2009). Phosphodiesterase 8B Gene Polymorphism is Associated with Subclinical Hypothyroidism in Pregnancy. Endocrinology, 150(11), 5191-5191.
Shields BM, Freathy RM, Knight BA, Hill A, Weedon MN, Frayling TM, Hattersley AT, Vaidya B (2009). Phosphodiesterase 8B gene polymorphism is associated with subclinical hypothyroidism in pregnancy.
J Clin Endocrinol Metab,
94(11), 4608-4612.
Abstract:
Phosphodiesterase 8B gene polymorphism is associated with subclinical hypothyroidism in pregnancy.
BACKGROUND: Maternal subclinical hypothyroidism is associated with a number of adverse outcomes in pregnancy. The Endocrine Society's recent consensus guidelines have recommended treatment with T(4) for this condition in pregnancy. The single nucleotide polymorphism rs4704397 in the phosphodiesterase 8B (PDE8B) gene has been found to be associated with altered serum TSH concentrations in the general population. We aimed to assess whether genetic variation in TSH due to the rs4704397 genotype affects the number of individuals classified as having subclinical hypothyroidism in pregnancy. METHODS: Serum TSH, FT4, FT3, and thyroid peroxidase antibodies (TPOAbs) were measured in 970 pregnant women at 28 wk gestation. rs4704397 genotype was available on 877 subjects. Reference range calculations were based on the TPOAb-negative women. RESULTS: TSH, but not FT4, FT3, or TPOAbs, varied with genotype and was highest in those with the AA genotype (median, 2.16, 1.84, and 1.73 mIU/liter for AA, AG, and GG genotypes, respectively; P = 0.0004). A greater proportion of women with the AA genotype had TSH concentrations above 4.21 mIU/liter, the upper limit of the reference range, compared with the AG and GG genotypes (9.6 vs. 3.5%, respectively; P = 0.004). Maternal PDE8B genotype was not associated with offspring birthweight or gestational age at delivery. CONCLUSION: Genetic variation in TSH levels in pregnancy associated with the PDE8B rs4704397 genotype has implications for the number of women treated for subclinical hypothyroidism under current guidelines. Consideration should be made to individualization of normal ranges, potential effects on pregnancy outcome, and intention to treat for subclinical hypothyroidism in pregnancy.
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Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A, Mlynarski W, Malecki MT, Hattersley AT, Ellard S, et al (2009). Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births.
Diabetologia,
52(8), 1683-1685.
Author URL.
Ellard S, Shields B, Tysoe C, Treacy R, Yau S, Mattocks C, Wallace A (2009). Semi-automated unidirectional sequence analysis for mutation detection in a clinical diagnostic setting.
Genet Test Mol Biomarkers,
13(3), 381-386.
Abstract:
Semi-automated unidirectional sequence analysis for mutation detection in a clinical diagnostic setting.
BACKGROUND: the past 10 years have seen an improvement in sequence data quality due to the introduction of capillary sequencers and new sequencing chemistries. In parallel, new software programs for automated mutation detection have been developed. We evaluated the sensitivity of semiautomated unidirectional sequence analysis for the detection of heterozygous base substitutions using the Mutation Surveyor software package. METHODS: Detection rates for heterozygous base substitutions in 29 genes by automated and visual inspection were compared. Examples of heterozygous bases not detected in one direction during bidirectional analysis were also sought through a national survey of United Kingdom (UK) genetics laboratories. Sequence quality was assessed in a consecutive cohort of 50 patients for whom the 39 exons of the ABCC8 gene had been sequenced in one direction. RESULTS: a total of 701 different heterozygous base substitutions were detected by the software with no false negatives (sensitivity >or=99.57%). Four examples of heterozygous bases missed in one direction during bidirectional analysis were reported. Two were detected using unidirectional analysis settings, and the other two bases had low-quality scores. of the 1950 amplicons examined, 97.2% had a quality score >or=30 and an average PHRED-like score >or=50 for the defined region of interest, and 98.1% of the 323,650 bases had a PHRED score >40. CONCLUSIONS: We found no evidence to support a requirement for bidirectional sequencing. Semiautomated analysis of good quality unidirectional sequence data has high sensitivity and is suitable for heterozygote mutation scanning in clinical diagnostic laboratories. Further work is required to determine minimum quality parameters for semiautomated analysis.
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McDonald TJ, Knight BA, Shields BM, Bowman P, Salzmann MB, Hattersley AT (2009). Stability and reproducibility of a single-sample urinary C-peptide/creatinine ratio and its correlation with 24-h urinary C-peptide.
Clin Chem,
55(11), 2035-2039.
Abstract:
Stability and reproducibility of a single-sample urinary C-peptide/creatinine ratio and its correlation with 24-h urinary C-peptide.
INTRODUCTION: C-peptide measurement in blood or 24-h urine samples provides useful information regarding endogenous insulin secretion, but problems related to the rapid degradation of C-peptide in blood and difficulty of 24-h urine collection have limited widespread routine clinical use of this test. We assessed the feasibility of measuring urinary C-peptide (UCP) with correction for creatinine concentration in single urine samples. METHODS: We analyzed UCP using a routine electrochemiluminescence immunoassay in samples from 21 healthy volunteers. We investigated the stability of UCP with different preservatives and storage conditions and compared the reproducibility of urinary C-peptide/creatinine ratio (UCPCR) in first- and second-void fasting urines, then assessed correlations with 24-h collections. RESULTS: UCPCR was unchanged at room temperature for 24 h and at 4 degrees C for 72 h even in the absence of preservative. UCPCR collected in boric acid was stable at room temperature for 72 h. UCPCR remained stable after 7 freeze-thaw cycles but decreased with freezer storage time and dropped to 82%-84% of baseline by 90 days at -20 degrees C. Second-void fasting UCPCRs were lower than first-void (median 0.78 vs 1.31, P = 0.0003) and showed less variation (CV 33% vs 52%), as second-void UCPCRs were not influenced by evening food-related insulin secretion. Second-void fasting UCPCR was highly correlated with 24-h UCP (r = 0.8, P = 0.00006). CONCLUSIONS: Second-void fasting UCPCR is a reproducible measure that correlates well with 24-h UCP in normal samples. The 3-day stability of UCPCR at room temperature greatly increases its potential clinical utility.
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Freathy RM, Bennett AJ, Ring SM, Shields B, Groves CJ, Timpson NJ, Weedon MN, Zeggini E, Lindgren CM, Lango H, et al (2009). Type 2 diabetes risk alleles are associated with reduced size at birth.
Diabetes,
58(6), 1428-1433.
Abstract:
Type 2 diabetes risk alleles are associated with reduced size at birth.
OBJECTIVE: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS: We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS: Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
Abstract.
Author URL.
Panicker V, Cluett C, Shields B, Murray A, Parnell KS, Perry JRB, Weedon MN, Singleton A, Hernandez D, Evans J, et al (2008). A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine.
J Clin Endocrinol Metab,
93(8), 3075-3081.
Abstract:
A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine.
INTRODUCTION: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. METHODS: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation. RESULTS: a SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. CONCLUSIONS: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.
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Author URL.
Freathy RM, Timpson NJ, Lawlor DA, Pouta A, Ben-Shlomo Y, Ruokonen A, Ebrahim S, Shields B, Zeggini E, Weedon MN, et al (2008). Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI.
Diabetes,
57(5), 1419-1426.
Abstract:
Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI.
OBJECTIVE: Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits. RESEARCH DESIGN AND METHODS: We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations. RESULTS: Each copy of the FTO rs9939609 a allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.048]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)). CONCLUSIONS: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.
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Author URL.
Rafiq M, Flanagan SE, Patch A-M, Shields BM, Ellard S, Hattersley AT, Neonatal Diabetes International Collaborative Group (2008). Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations.
Diabetes Care,
31(2), 204-209.
Abstract:
Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations.
OBJECTIVE: Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K(+) channel. Transfer from insulin to oral sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the response to sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 mutations. RESEARCH DESIGN AND METHODS: We followed 27 patients with SUR1 mutations for at least 2 months after attempted transfer to sulfonylureas. Information was collected on clinical features, treatment before and after transfer, and the transfer protocol used. We compared successful and unsuccessful transfer patients, glycemic control before and after transfer, and treatment requirements in patients with SUR1 and Kir6.2 mutations. RESULTS: Twenty-three patients (85%) successfully transferred onto sulfonylureas without significant side effects or increased hypoglycemia and did not need insulin injections. In these patients, median A1C fell from 7.2% (interquartile range 6.6-8.2%) on insulin to 5.5% (5.3-6.2%) on sulfonylureas (P = 0.01). When compared with Kir6.2 patients, SUR1 patients needed lower doses of both insulin before transfer (0.4 vs. 0.7 units x kg(-1) x day(-1); P = 0.002) and sulfonylureas after transfer (0.26 vs. 0.45 mg x kg(-1) x day(-1); P = 0.005). CONCLUSIONS: Oral sulfonylurea therapy is safe and effective in the short term in most patients with diabetes due to SUR1 mutations and may successfully replace treatment with insulin injections. A different treatment protocol needs to be developed for this group because they require lower doses of sulfonylureas than required by Kir6.2 patients.
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Author URL.
Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JRB, Stevens S, Hall AS, et al (2008). Genome-wide association analysis identifies 20 loci that influence adult height.
Nat Genet,
40(5), 575-583.
Abstract:
Genome-wide association analysis identifies 20 loci that influence adult height.
Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.
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Author URL.
Edghill EL, Flanagan SE, Patch A-M, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, et al (2008). Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.
Diabetes,
57(4), 1034-1042.
Abstract:
Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.
OBJECTIVE: Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. RESEARCH DESIGN AND METHODS: the INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed
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Author URL.
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PIW, Abecasis GR, Almgren P, Andersen G, et al (2008). Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
Nat Genet,
40(5), 638-645.
Abstract:
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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Author URL.
Shields BM, Spyer G, Slingerland AS, Knight BA, Ellard S, Clark PM, Hauguel-de Mouzon S, Hattersley AT (2008). Mutations in the glucokinase gene of the fetus result in reduced placental weight.
Diabetes Care,
31(4), 753-757.
Abstract:
Mutations in the glucokinase gene of the fetus result in reduced placental weight.
OBJECTIVE: in human pregnancy, placental weight is strongly associated with birth weight. It is uncertain whether there is regulation of the placenta by the fetus or vice versa. We aimed to test the hypothesis that placental growth is mediated, either directly or indirectly, by fetal insulin. RESEARCH DESIGN AND METHODS: Birth weight and placental weight were measured in 43 offspring of 21 parents with mutations in the glucokinase (GCK) gene (25 had inherited the mutation and 18 had not), which results in reduced fetal insulin secretion. Birth weight, placental weight, umbilical cord insulin, and maternal glucose and insulin concentrations were measured in 573 nondiabetic, healthy, term pregnancies. RESULTS: GCK mutation carriers were lighter and also had smaller placentas (610 vs. 720 g, P = 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P = 0.003). GCK mRNA was not detected in the placenta by RT-PCR. In the normal pregnancies, placental weight was strongly correlated with birth weight (r = 0.61, P < 0.001). Cord insulin concentrations were directly related to placental weight (r = 0.28) and birth weight (r = 0.36) (P < 0.001 for both). CONCLUSIONS: These results suggest that insulin, directly or indirectly, plays a role in placental growth, especially as a mutation in the GCK gene, which is known to only alter fetal insulin secretion, results in altered placental weight. This finding is consistent with the preferential localization of the insulin receptors in the fetal endothelium of the placenta in the last trimester of pregnancy.
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Author URL.
Harries LW, Locke JM, Shields B, Hanley NA, Hanley KP, Steele A, Njølstad PR, Ellard S, Hattersley AT (2008). The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development.
Diabetes,
57(6), 1745-1752.
Abstract:
The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development.
OBJECTIVE: Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype. RESEARCH DESIGN AND METHODS: We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations. RESULTS: HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4-6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P < 0.00001). CONCLUSIONS: We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.
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Author URL.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JRB, Elliott KS, Lango H, Rayner NW, et al (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
Science,
316(5826), 889-894.
Abstract:
A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
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Author URL.
Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JRB, Elliott KS, Hackett R, Guiducci C, Shields B, et al (2007). A common variant of HMGA2 is associated with adult and childhood height in the general population.
Nat Genet,
39(10), 1245-1250.
Abstract:
A common variant of HMGA2 is associated with adult and childhood height in the general population.
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 x 10(-11), overall P = 4 x 10(-16), including the genome-wide association data). We also observed the association in children (P = 1 x 10(-6), N = 6,827) and a tall/short case-control study (P = 4 x 10(-6), N = 3,207). We estimate that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.
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Author URL.
Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, et al (2007). Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
Nat Genet,
39(11), 1329-1337.
Abstract:
Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
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Author URL.
Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, Bilous R (2007). Brief report: Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding?.
Journal of Clinical Endocrinology and Metabolism,
92(1), 203-207.
Abstract:
Brief report: Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding?
Context: Maternal subclinical hypothyroidism during pregnancy is associated with various adverse outcomes. Recent consensus guidelines do not advocate universal thyroid function screening during pregnancy but recommend testing high-risk pregnant women with a personal history of thyroid or other autoimmune disorders or with a family history of thyroid disorders. Objective: the objective of the study was to assess efficacy of the targeted high-risk case-finding approach in identifying women with thyroid dysfunction during early pregnancy. Design/Setting: This was a single-center cohort study. Patients/Outcome Measures: We prospectively analyzed TSH, free T4 and free T3 in 1560 consecutive pregnant women during their first antenatal visit (median gestation 9 wk). We tested thyroperoxidase antibodies in 1327 (85%). We classified 413 women (26.5%), who had a personal history of thyroid or other autoimmune disorders or a family history of thyroid disorders, as a high-risk group. We examined whether testing only such a high-risk group would pick up most pregnant women with thyroid dysfunction. Results: Forty women (2.6%) had raised TSH (>4.2 mIU/liter). The prevalence of raised TSH was higher in the high-risk group [6.8 vs. 1% in the low-risk group, relative risk (RR) 6.5, 95% confidence interval (CI) 3.3-12.6, P < 0.0001]. Presence of personal history of thyroid disease (RR 12.2, 95% CI 6.8-22, P < 0.0001) or other autoimmune disorders (RR 4.8, 95% CI 1.3-18.2, P < 0.016), thyroperoxidase antibodies (RR 8.4, 95% CI 4.6-15.3, P < 0.0001), and family history of thyroid disorders (RR 3.4, 95% CI 1.8-6.2, P < 0.0001) increased the risk of raised TSH. However, 12 of 40 women with raised TSH (30%) were in the low-risk group. Conclusion: Targeted thyroid function testing of only the high-risk group would miss about one third of pregnant women with overt/subclinical hypothyroidism. Copyright © 2007 by the Endocrine Society.
Abstract.
MWeedon, Fawcett KA, Sandhu MS, Wasson J (2007). Common variants in WFS1 confer risk of type 2 diabetes. Nature Genetics, 39(10), 951-953.
Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, Bilous R (2007). Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding?.
J Clin Endocrinol Metab,
92(1), 203-207.
Abstract:
Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding?
CONTEXT: Maternal subclinical hypothyroidism during pregnancy is associated with various adverse outcomes. Recent consensus guidelines do not advocate universal thyroid function screening during pregnancy but recommend testing high-risk pregnant women with a personal history of thyroid or other autoimmune disorders or with a family history of thyroid disorders. OBJECTIVE: the objective of the study was to assess efficacy of the targeted high-risk case-finding approach in identifying women with thyroid dysfunction during early pregnancy. DESIGN/SETTING: This was a single-center cohort study. PATIENTS/OUTCOME MEASURES: We prospectively analyzed TSH, free T4 and free T3 in 1560 consecutive pregnant women during their first antenatal visit (median gestation 9 wk). We tested thyroperoxidase antibodies in 1327 (85%). We classified 413 women (26.5%), who had a personal history of thyroid or other autoimmune disorders or a family history of thyroid disorders, as a high-risk group. We examined whether testing only such a high-risk group would pick up most pregnant women with thyroid dysfunction. RESULTS: Forty women (2.6%) had raised TSH (>4.2 mIU/liter). The prevalence of raised TSH was higher in the high-risk group [6.8 vs. 1% in the low-risk group, relative risk (RR) 6.5, 95% confidence interval (CI) 3.3-12.6, P < 0.0001]. Presence of personal history of thyroid disease (RR 12.2, 95% CI 6.8-22, P < 0.0001) or other autoimmune disorders (RR 4.8, 95% CI 1.3-18.2, P = 0.016), thyroperoxidase antibodies (RR 8.4, 95% CI 4.6-15.3, P < 0.0001), and family history of thyroid disorders (RR 3.4, 95% CI 1.8-6.2, P < 0.0001) increased the risk of raised TSH. However, 12 of 40 women with raised TSH (30%) were in the low-risk group. CONCLUSION: Targeted thyroid function testing of only the high-risk group would miss about one third of pregnant women with overt/subclinical hypothyroidism.
Abstract.
Author URL.
Nejentsev S, Howson JMM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, et al (2007). Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.
Nature,
450(7171), 887-892.
Abstract:
Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A
The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group.
Abstract.
Shields BM, Knight B, Hopper H, Hill A, Powell RJ, Hattersley AT, Clark PM (2007). Measurement of cord insulin and insulin-related peptides suggests that girls are more insulin resistant than boys at birth.
Diabetes Care,
30(10), 2661-2666.
Abstract:
Measurement of cord insulin and insulin-related peptides suggests that girls are more insulin resistant than boys at birth.
OBJECTIVE: We aimed to examine sex differences in insulin and insulin propeptide concentrations at birth using validated cord blood collection. RESEARCH DESIGN AND METHODS: We tested the impact on insulin and insulin propeptides of taking 13 cord blood samples in heparin and EDTA and then centrifuging and separating plasma after 1, 2, 24, or 48 h at room temperature (heparin) or 4 degrees C (EDTA). Cord plasma insulin and insulin propeptides concentrations were measured in 440 babies and correlated with offspring anthropometry measured at birth. RESULTS: Cord insulin concentrations significantly decreased (74% those at baseline by 24 h; P = 0.01) in the samples taken in heparin and stored at room temperature, but those taken on EDTA and refrigerated remained stable for up to 48 h. Insulin propeptides were stable in both. Cord plasma insulin and insulin propeptides measured in EDTA were related to all measures of birth size and maternal glycemia and BMI (r > 0.11; P < 0.03 for all) and were higher in those delivered via caesarean section. Girls were lighter (3,497 vs. 3,608 g; P = 0.01) but had higher cord insulin (46.7 vs. 41.2 pmol/l; P = 0.031), total proinsulin (34.1 vs. 25.8 pmol/l; P < 0.001), and intact proinsulin (9.5 vs. 8.3 pmol/l; P = 0.004) concentrations than boys; this was further confirmed when cord insulin concentrations of boys and girls were compared after pair matching for birth weight (insulin 49.7 vs. 42.1 pmol/l; P = 0.004). CONCLUSIONS: When using appropriate sample collection methods, female newborns have higher insulin concentrations than male newborns, despite being smaller, suggesting intrinsic insulin resistance in girls.
Abstract.
Author URL.
Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JRB, Rayner NW, Freathy RM, et al (2007). Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
Science,
316(5829), 1336-1341.
Abstract:
Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
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Author URL.
Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, Donn R, Symmons DP, Hider S, Bruce IN, et al (2007). Rheumatoid arthritis association at 6q23.
Nature Genetics,
39(12), 1431-1433.
Abstract:
Rheumatoid arthritis association at 6q23
The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 × 10 -5 - 5 × 10-7 in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 × 10 -8) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-α-induced protein 3 (TNFAIP3). © 2007 Nature Publishing Group.
Abstract.
Knight B, Shields BM, Hill A, Powell RJ, Wright D, Hattersley AT (2007). The impact of maternal glycemia and obesity on early postnatal growth in a nondiabetic Caucasian population.
Diabetes Care,
30(4), 777-783.
Abstract:
The impact of maternal glycemia and obesity on early postnatal growth in a nondiabetic Caucasian population.
OBJECTIVE: Offspring of mothers with diabetes have increased birth weight and higher rates of obesity in early childhood. The relative role of maternal glycemia and maternal obesity is uncertain. We therefore studied the impact of maternal glycemia and maternal obesity on offspring birth measures and early postnatal growth in nondiabetic pregnancies. RESEARCH DESIGN AND METHODS: We studied 547 full-term singleton babies of nondiabetic parents. Data available included parental height and weight; maternal prepregnant weight; maternal fasting plasma glucose (FPG) at 28 weeks of gestation; and offspring weight and length at birth, 12 weeks of age, and 1 and 2 years of age. Relationships between parental and offspring measures were estimated using Pearson correlations. RESULTS: Maternal FPG was correlated with offspring birth weight (r = 0.25, P < 0.001), length (r = 0.17, P < 0.001), and BMI (r = 0.2, P < 0.001) but was not correlated with offspring growth at 12 weeks. Maternal prepregnancy BMI was significantly correlated with offspring weight (r = 0.26, P < 0.001), length (r = 0.12, P = 0.01), and BMI at birth (r = 0.26, P < 0.001) and remained correlated with offspring weight (r = 0.13-0.14, P = 0.007-0.002) and BMI (r = 0.14-0.19, P = 0.002 to
Abstract.
Author URL.
De Silva NMG, Steele A, Shields B, Knight B, Parnell K, Weedon MN, Hattersley AT, Frayling TM (2007). The transcription factor 7-like 2 (TCF7L2) gene is associated with Type 2 diabetes in UK community-based cases, but the risk allele frequency is reduced compared with UK cases selected for genetic studies.
Diabet Med,
24(10), 1067-1072.
Abstract:
The transcription factor 7-like 2 (TCF7L2) gene is associated with Type 2 diabetes in UK community-based cases, but the risk allele frequency is reduced compared with UK cases selected for genetic studies.
AIMS: Common polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies. METHODS: We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged > or = 45 years (community control subjects). RESULTS: When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13-1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38-1.80), P = 1.4 x 10(-11)] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41-1.54), P < 10(-20)]. CONCLUSION: Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects.
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Author URL.
Freathy RM, Weedon MN, Bennett A, Hypponen E, Relton CL, Knight B, Shields B, Parnell KS, Groves CJ, Ring SM, et al (2007). Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals.
Am J Hum Genet,
80(6), 1150-1161.
Abstract:
Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals.
The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.
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Author URL.
TFrayling, Clark VJ, Qian Y, Weedon MN (2006). A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses. The American Journal of Human Genetics, 79(6), 991-1001.
Weedon MN, Clark VJ, Qian Y, Ben-Shlomo Y, Timpson N, Ebrahim S, Lawlor DA, Pembrey ME, Ring S, Wilkin TJ, et al (2006). A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.
Am J Hum Genet,
79(6), 991-1001.
Abstract:
A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.
Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal a allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.
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Author URL.
Freathy RM, Mitchell SMS, Knight B, Shields B, Weedon MN, Hattersley AT, Frayling TM (2006). A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population.
J Negat Results Biomed,
5Abstract:
A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population.
BACKGROUND: Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers. RESULTS: We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes. CONCLUSION: We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study.
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Author URL.
Porter JR, Rangasami JJ, Ellard S, Gloyn AL, Shields BM, Edwards J, Anderson JM, Shaw NJ, Hattersley AT, Frayling TM, et al (2006). Asian MODY: are we missing an important diagnosis?.
Diabet Med,
23(11), 1257-1260.
Abstract:
Asian MODY: are we missing an important diagnosis?
AIMS: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes where correct diagnosis alters treatment, prognosis and genetic counselling. The first UK survey of childhood MODY identified 20 White, but no Asian children with MODY. We hypothesized that MODY causes diabetes in UK Asians, but is underdiagnosed. METHODS: Children with dominant family histories of diabetes were recruited. Direct sequencing for mutations in the two most common MODY genes; HNF1A (TCF1) and GCK was performed in autoantibody-negative probands. We also compared MODY testing data for Asian and White cases from the Exeter MODY database, to 2001 UK census data. RESULTS: We recruited 30 families and identified three Asian families with MODY gene mutations (two HNF1A, one GCK) and three White UK families (two HNF1A, one GCK). Heterozygous MODY phenotypes were similar in Asians and Whites. Only eight (0.5%) of 1369 UK referrals for MODY testing were known to be Asian, but in 2001 Asians represented 4% of the English/Welsh population and have a higher prevalence of diabetes. CONCLUSIONS: We identified three cases of childhood MODY in UK Asians and demonstrated reduced rates of MODY testing in Asians, which has negative implications for treatment. It is unclear why this is. MODY should be considered in autoantibody-negative Asian diabetes patients lacking evidence of insulin resistance.
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Author URL.
Shields BM, Knight BA, Powell RJ, Hattersley AT, Wright DE (2006). Assessing newborn body composition using principal components analysis: differences in the determinants of fat and skeletal size.
BMC Pediatr,
6Abstract:
Assessing newborn body composition using principal components analysis: differences in the determinants of fat and skeletal size.
BACKGROUND: Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components. METHODS: Weight, length, crown-rump, knee-heel, head circumference, arm circumference, and skinfold thicknesses were measured at birth in 699 healthy, term, UK babies recruited as part of the Exeter Family Study of Childhood Health. Corresponding measurements were taken on both parents. Principal components analysis with varimax rotation was used to reduce these measurements to two independent components each for mother, father and baby: one highly correlated with measures of fat, the other with skeletal size. RESULTS: Gestational age was significantly related to skeletal size, in both boys and girls (r = 0.41 and 0.52), but not fat. Skeletal size at birth was also associated with parental skeletal size (maternal: r = 0.24 (boys), r = 0.39 (girls) ; paternal: r = 0.16 (boys), r = 0.25 (girls)), and maternal smoking (0.4 SD reduction in boys, 0.6 SD reduction in girls). Fat was associated with parity (first borns smaller by 0.45 SD in boys; 0.31 SD in girls), maternal glucose (r = 0.18 (boys); r = 0.27 (girls)) and maternal fat (r = 0.16 (boys); r = 0.36 (girls)). CONCLUSION: Principal components analysis with varimax rotation provides a useful method for reducing birth weight to two more meaningful components: skeletal size and fat. These components have different associations with known determinants of birth weight, suggesting fat and skeletal size may have different regulatory mechanisms, which would be important to consider when studying the associations of birth weight with later adult disease.
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Author URL.
Weedon MN, McCarthy MI, Hitman G, Walker M, Groves CJ, Zeggini E, Rayner NW, Shields B, Owen KR, Hattersley AT, et al (2006). Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.
PLoS Med,
3(10).
Abstract:
Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.
BACKGROUND: a limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (approximately 20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. METHODS AND FINDINGS: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. CONCLUSIONS: Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.
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Shields BM, Knight B, Shakespeare L, Babrah J, Powell RJ, Clark PM, Hattersley AT (2006). Determinants of insulin concentrations in healthy 1-week-old babies in the community: applications of a bloodspot assay.
Early Hum Dev,
82(2), 143-148.
Abstract:
Determinants of insulin concentrations in healthy 1-week-old babies in the community: applications of a bloodspot assay.
BACKGROUND: Epidemiological research into insulin secretion and insulin action would be helped by improved ability to measure insulin concentrations in large groups of healthy babies in the neonatal period. Such research is often restricted by the invasive nature of blood sampling. AIMS: We assessed the use of an assay that can measure insulin from bloodspots taken during routine Guthrie testing 7 days after delivery. STUDY DESIGN AND SUBJECTS: Insulin and glucose were measured in 366 seven-day-old infants from heel-prick bloodspots. Time since last feed and type of feed were recorded. RESULTS: Bloodspot insulin concentrations in normal 7-day-old infants were much lower (median (IQR): 15.4 pmol/l (
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Freathy RM, Weedon MN, Shields B, Hitman GA, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2006). Functional variation in VEGF is not associated with type 2 diabetes in a United Kingdom Caucasian population.
JOP,
7(3), 295-302.
Abstract:
Functional variation in VEGF is not associated with type 2 diabetes in a United Kingdom Caucasian population.
CONTEXT: Vascular endothelial growth factor (VEGF) is important for pancreatic beta cell development and function. Common variation in the VEGF gene is associated with altered serum concentrations of VEGF and with several diseases, but its role in type 2 diabetes is not known. The single nucleotide polymorphisms C-2578A (rs699947), G-1154A (rs1570360) and G-634C (rs2010963) in the 5'-region of VEGF are associated with altered serum concentrations of the protein. OBJECTIVE: We performed a large case-control and family-based study to test the hypothesis that these variants are associated with type 2 diabetes in a UK Caucasian population. PARTICIPANTS: We genotyped 1,969 cases, 1,625 controls and 530 families for the three single nucleotide polymorphisms. MAIN OUTCOME MEASURES: Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of alleles to affected offspring. RESULTS: Despite good power (80%) to detect odds ratios of approximately 1.2, there were no significant associations between single alleles or genotypes and type 2 diabetes. Odds ratios (and 95% confidence intervals) comparing case and control allele frequencies for single nucleotide polymorphisms C-2578A, G-1154A and G-634C were 0.97 (0.88-1.07), 0.99 (0.90-1.09) and 0.97 (0.88-1.08), respectively. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in VEGF and type 2 diabetes risk. We have found no evidence that these three single nucleotide polymorphisms, shown previously to alter VEGF concentrations, are risk factors for type 2 diabetes in a large UK Caucasian case-control and family-based study.
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Castleden HAJ, Shields B, Bingley PJ, Williams AJK, Sampson M, Walker M, Gibson JM, McCarthy MI, Hitman GA, Levy JC, et al (2006). GAD antibodies in probands and their relatives in a cohort clinically selected for Type 2 diabetes.
Diabet Med,
23(8), 834-838.
Abstract:
GAD antibodies in probands and their relatives in a cohort clinically selected for Type 2 diabetes.
AIMS: a subset of patients who present as if they have Type 2 diabetes have positive pancreatic autoantibodies, and have been referred to as having latent autoimmune diabetes in adults (LADA). We assessed the prevalence and clinical characteristics of patients with glutamic acid decarboxylase antibodies (GADA) in a cohort clinically selected for Type 2 diabetes and determined the presence of diabetes and GADA in their first-degree relatives. METHODS: GADA were measured in 2059 subjects, not known to be related, and clinically selected as having Type 2 diabetes for genetic studies. Clinical characteristics were compared in GADA positive and GADA negative subjects. Diabetes and GAD antibody status were compared in 208 first-degree relatives of GADA positive and GADA negative probands. RESULTS: of the subjects, 136 (7%) were GADA positive. Compared with the GADA negative subjects, they were slimmer (P < 0.001), diagnosed at a younger age (P = 0.011) and progressed to insulin faster (P < 0.001). Thirty-three per cent of GADA positive subjects had a first-degree relative with diabetes compared with 42% of GADA negative subjects (P = 0.034). The overall prevalence of GADA was similar in the first-degree relatives of GADA positive and GADA negative probands (4 v 5%), and 19 of 22 (86%) diabetic relatives of GADA positive probands were GADA negative. CONCLUSION: Despite clinically selecting a Type 2 diabetes cohort, 7% were GADA positive with an altered phenotype. These GADA positive patients had a strong family history of non-autoimmune diabetes. This suggests that, in this subgroup of patients, autoimmune pancreatic beta-cell destruction occurs on a background of Type 2 diabetes genetic susceptibility.
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Weedon MN, Shields B, Hitman G, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2006). No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians.
Diabetes,
55(11), 3175-3179.
Abstract:
No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians.
Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-induced activation of the insulin receptor. There is strong evidence from several previous studies that a common coding variant of ENPP1 (K121Q) and a three-marker haplotype (Q121, IVS20delT-11, and G+1044TGA) are associated with type 2 diabetes and obesity. We examined the impact of ENPP1 variation on type 2 diabetes and obesity in a large U.K. genetic association study. We genotyped the three previously associated polymorphisms in 2,363 type 2 diabetic case and 4,045 control subjects, as well as 1,681 subjects from 529 type 2 diabetic families. We used the same subjects for morbid and moderate obesity association studies. For type 2 diabetes, moderate and morbid obesity, and for both the Q121 and three-marker haplotype, our results exclude with >95% confidence the effect sizes from previous studies (Q121 allele: odds ratio 1.02 [95% CI 0.93-1.12], P = 0.61; 1.00 [0.85-1.18], P = 0.99; and 0.92 [0.70-1.20], P = 0.41; three-marker haplotype: 1.10 [0.96-1.26], P = 0.17; 0.97 [0.77-1.23], P = 0.81; and 0.86 [0.57-1.30], P = 0.46 for type 2 diabetes, moderate, and morbid obesity, respectively). A K121Q type 2 diabetes meta-analysis of all previously published studies remained significant after the inclusion of this study (1.25 [1.10-1.43], P = 0.0007), although there was some evidence of publication bias. In conclusion, we find no evidence that previously associated variants of ENPP1 are associated with type 2 diabetes or obesity in the U.K. population.
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Knight B, Shields BM, Hill A, Powell RJ, Round A, Hamilton W, Hattersley AT (2006). Offspring birthweight is not associated with paternal insulin resistance.
Diabetologia,
49(11), 2675-2678.
Abstract:
Offspring birthweight is not associated with paternal insulin resistance.
AIMS/HYPOTHESIS: Low birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight. SUBJECTS AND METHODS: the Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee. RESULTS: Offspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=-0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight. CONCLUSIONS/INTERPRETATION: Results from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.
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Shields BM, Knight B, Turner M, Wilkins-Wall B, Shakespeare L, Powell RJ, Hannemann M, Clark PM, Yajnik CS, Hattersley AT, et al (2006). Paternal insulin resistance and its association with umbilical cord insulin concentrations.
Diabetologia,
49(11), 2668-2674.
Abstract:
Paternal insulin resistance and its association with umbilical cord insulin concentrations.
AIMS/HYPOTHESIS: Fetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factors may alter fetal insulin secretion and insulin action. SUBJECTS, MATERIALS AND METHODS: to assess this, we analysed plasma insulin concentration in umbilical cord blood from 644 normal, term, UK Caucasian deliveries from the Exeter Family Study of Childhood Health. We tested for associations between cord insulin and each of parental anthropometry, fasting glucose, insulin and lipids. RESULTS: As expected, cord insulin concentrations correlated with all measures of birth size (weight, length, head and arm circumferences, sum of skinfold thicknesses, ponderal index: r=0.16-0.4, p
Abstract.
Author URL.
Knight B, Shields BM, Hattersley AT (2006). The Exeter Family Study of Childhood Health (EFSOCH): study protocol and methodology.
Paediatr Perinat Epidemiol,
20(2), 172-179.
Abstract:
The Exeter Family Study of Childhood Health (EFSOCH): study protocol and methodology.
The Exeter Family Study of Childhood Health is a prospective study, set up to test the fetal insulin hypothesis, and to identify genetic polymorphisms that play a role in determining birthweight and early postnatal growth. We recruited 1017 families from a postcode-defined area in central Exeter. Specific inclusion criteria were established to obtain a homogeneous, non-diabetic, UK Caucasian cohort. Detailed anthropometric measurements were taken from both parents at 28 weeks' gestation, and from their children at birth, 12 weeks, 1 year and 2 years of age. Insulin and other biochemical analysis were measured in fasting parental samples and an umbilical cord blood sample taken at delivery. Parental and offspring DNA were extracted to allow molecular genetic analysis of candidate genes implicated in fetal growth. This comprehensive data set is available on a disease-free cohort, and detailed preparatory work has ensured high levels of quality control. The study would welcome collaboration within strict confidentiality rules.
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Freathy RM, Weedon MN, Melzer D, Shields B, Hitman GA, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2006). The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians.
BMC Med Genet,
7Abstract:
The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians.
BACKGROUND: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. METHODS: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. RESULTS: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study.
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Author URL.
Weedon MN, Owen KR, Shields B, Hitman G, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2005). A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population.
Diabetes,
54(8), 2487-2491.
Abstract:
A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population.
HNF1alpha (TCF1) is a key transcription factor that is essential for pancreatic beta-cell development and function. Rare mutations of HNF1alpha cause maturity-onset diabetes of the young. A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1alpha variation in European populations has not been comprehensively assessed. We determined the linkage disequilibrium and haplotype structure across the HNF1alpha gene region using 29 single nucleotide polymorphisms (SNPs). Eight tagging SNPs (tSNPs) that efficiently capture common haplotypes and the amino acid-changing variant, A98V, were genotyped in 5,307 subjects (2,010 type 2 diabetic case subjects, 1,643 control subjects, and 1,654 members of 521 families). We did not find any evidence of association between the tSNPs or haplotypes and type 2 diabetes. We could exclude odds ratios (ORs) >1.25 for all tSNPs. The rare V98 allele (approximately 3% frequency) showed possible evidence of association with type 2 diabetes (OR 1.23 [95% CI 0.99-1.54], P = 0.07), a result that was supported by meta-analysis of this and published studies (OR 1.31 [1.08-1.59], P = 0.007). Further studies are required to investigate this association, demonstrating the difficulty of defining the role of rare (
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Knight B, Shields BM, Turner M, Powell RJ, Yajnik CS, Hattersley AT (2005). Evidence of genetic regulation of fetal longitudinal growth.
Early Hum Dev,
81(10), 823-831.
Abstract:
Evidence of genetic regulation of fetal longitudinal growth.
BACKGROUND: Genetic as well as environmental factors are important determinants of fetal growth but there have been few studies of the influence of paternal factors on fetal growth. AIM: to study the influence of paternal anthropometry on detailed measurements of offspring at birth. DESIGN: a prospective cohort study involving biochemistry, and anthropometry, of mothers and fathers at 28 weeks gestation, and detailed anthropometry of children within 24 h of birth. SUBJECTS: 567 White Caucasian singleton, non-diabetic, full term pregnancies recruited from central Exeter, UK. RESULTS: Paternal height, but not paternal BMI, was correlated with birth weight (r = 0.19) and with birth length (r = 0.33). This was independent of potential confounders and maternal height. All measurements of fetal skeletal growth including crown-rump, knee-heel and head circumference were associated with paternal height. Maternal height showed similar correlations with birth weight (r = 0.18) and birth length (r = 0.26). Maternal BMI was correlated with birth weight (r = 0.27) and birth length (r = 0.15). In a multifactorial analysis 38% of the variance in fetal height could be explained by gestation, sex, paternal height, maternal height, maternal glucose, maternal BMI, parity and maternal smoking. CONCLUSION: Paternal height has an independent influence on size at birth. This predominantly influences length and skeletal growth of the baby. In contrast to maternal obesity the degree of paternal obesity does not influence birth weight. This work suggests that there is genetic regulation of skeletal growth while the maternal environment predominantly alters the adiposity of the fetus.
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Weedon MN, Frayling TM, Shields B, Knight B, Turner T, Metcalf BS, Voss L, Wilkin TJ, McCarthy A, Ben-Shlomo Y, et al (2005). Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.
Diabetes,
54(2), 576-581.
Abstract:
Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.
Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position -30 of the GCK beta-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the a allele at GCK(-30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The a allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(-30) on birth weight using 2,689 mother/child pairs. The presence of the a allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an a allele at GCK(-30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight.
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Weedon MN, Owen KR, Shields B, Hitman G, Walker M, McCarthy MI, Love-Gregory LD, Permutt MA, Hattersley AT, Frayling TM, et al (2004). Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population.
Diabetes,
53(11), 3002-3006.
Abstract:
Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population.
Hepatocyte nuclear factor (HNF)-4alpha is part of a transcription factor network that is key for the development and function of the beta-cell. Rare mutations in the HNF4alpha gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12-13.1 where the HNF4alpha gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12-13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02-1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12-13.1-linked cases. In conclusion, we have replicated the association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q.
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Levine L (2003). Lipids in Health and Disease, 2(1), 1-1.
Ward KJ, Shields B, Knight B, Salzmann MB, Hattersley AT, Frayling TM (2003). Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy.
Lipids Health Dis,
2Abstract:
Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy.
BACKGROUND: Triglyceride concentrations are raised in pregnancy and are considered a key fetal fuel. Several gene variants are known to alter triglyceride concentrations, including those in the Apolipoprotein E (ApoE), Lipoprotein Lipase (LPL), and most recently, the Apolipoprotein AV (ApoAV) gene. However, less is known about how variants in these genes alter triglyceride concentrations in pregnancy or affect fetal growth. We aimed to determine the effect of the recently identified ApoAV gene on triglycerides in pregnancy and fetal growth. We assessed the role of two ApoAV haplotypes, defined by the C and W alleles of the -1131T>C and S19W polymorphisms, in 483 pregnant women and their offspring from the Exeter Family Study of Childhood Health. RESULTS: the -1131T>C and S19W variants have rare allele frequencies of 6.7% and 4.9% and are present in 13.4% and 9.7% of subjects respectively. In carriers of the -1131C and 19W alleles triglyceride concentrations were raised by 11.0% (1.98 mmol/ l(1.92 - 2.04) to 2.20 mmol/l (2.01 - 2.42), p = 0.035; and 16.2% (1.97 mmol/l (1.91 - 2.03) to 2.29 mmol/l (2.12 - 2.48), p < 0.001 respectively. There is nominally significant evidence that the -1131T>C variant is having an effect on maternal height (164.9 cm (164.3 - 165.5) to 167.0 cm (165.2 - 168.8), p = 0.029). There was no evidence that ApoAV genotype alters any other anthropometric measurements or biochemistries such as High Density Lipoprotein Cholesterol (HDL-C) or Low Density Lipoprotein Cholesterol (LDL-C). There is nominally significant evidence that the presence of a maternal -1131C variant alters fetal birth length (50.2 cm (50.0 - 50.4) to 50.9 cm (50.3 - 51.4), p = 0.022), and fetal birth crown-rump length (34.0 cm (33.8 - 34.1) to 34.5 cm (34.1 - 35.0), p = 0.023). There is no evidence that ApoAV genotype alters fetal birth weight or other fetal growth measurements. CONCLUSION: in conclusion variation in the ApoAV gene raises triglyceride concentrations in pregnancy, as well as normolipaemic states and there is preliminary evidence that it alters fetal growth parameters.
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Mitchell SMS, Weedon MN, Owen KR, Shields B, Wilkins-Wall B, Walker M, McCarthy MI, Frayling TM, Hattersley AT (2003). Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects.
Diabetes,
52(5), 1276-1279.
Abstract:
Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects.
The orphan receptor small heterodimer partner (SHP, NR0B2) modulates the transcription activity of the MODY1 gene HNF4a. Mutations in SHP were found in 7% of Japanese obese young-onset type 2 diabetic patients and were associated with moderate obesity and increased birth weight. We investigated SHP in 1927 U.K. subjects, examining relationships with type 2 diabetes, obesity, and birth weight. Sequencing of the coding region of SHP in 122 obese, young-onset type 2 diabetic patients detected the polymorphism G171A. The polymorphism was not associated with diabetes in case control or familial association studies. The a allele (frequency 0.07) was not associated with obesity in type 2 diabetic subjects (n = 348), their parents (n = 272), or young nondiabetic adults (n = 925). However, the rare (
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