Publications by year
In Press
Green HD, Jones A, Evans JP, Wood AR, Beaumont RN, Tyrrell J, Frayling TM, Smith C, Weedon MN (In Press). A genome wide association study of frozen shoulder identifies a common variant of WNT7B and diabetes as causal risk factors.
Abstract:
A genome wide association study of frozen shoulder identifies a common variant of WNT7B and diabetes as causal risk factors
AbstractFrozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes.We performed a genome wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 2064 cases identified from ICD-10 codes. We used data from FinnGen for replication. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder.We identified a single genome-wide significant locus (lead SNP rs62228062; OR=1.34 [1.28-1.41], p=2×10−16) that contained WNT7B. A recent transcriptome study identified WNT7B as amongst the most enriched transcripts in anterior capsule tissue in patients undergoing arthroscopic capsulotomy surgery for frozen shoulder suggesting WNT7B as a potential causal gene at the locus. The lead SNP was also strongly associated with Dupuytren’s contracture (OR=2.61 [2.50, 2.72], p<1×10−100). The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR=1.04 [1.02-1.07], p=6×10−5). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects.We have identified the first genetic variant associated with frozen shoulder. WNT7B is a potential causal gene at the locus. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.
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2021
Nice R, Chanchlani N, Green H, Bewshea C, Ahmad T, Goodhand JR, McDonald TJ, Perry MH, Kennedy NA (2021). Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays.
Aliment Pharmacol Ther,
53(1), 128-137.
Abstract:
Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays.
BACKGROUND: When used proactively, drug-tolerant anti-tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity. AIM: to validate positivity thresholds of IDKmonitor drug-tolerant anti-infliximab and -adalimumab antibody assays. METHODS: We applied positivity thresholds, defined by testing sera from 498 anti-TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti-TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes. RESULTS: the 80% one-sided lower confidence interval of the 99th centile concentration for anti-infliximab and -adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab- than infliximab- (11.2% [814/7272] vs 3.1% [390/12 683] P
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2020
Lin S, Green HD, Hendy P, Heerasing NM, Chanchlani N, Hamilton B, Walker GJ, Heap GA, Hobart J, Martin RJ, et al (2020). Clinical features and genetic risk of demyelination following anti-TNF treatment.
J Crohns ColitisAbstract:
Clinical features and genetic risk of demyelination following anti-TNF treatment.
BACKGROUND: Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and test whether affected patients were genetically predisposed to multiple sclerosis (MS). METHODS: We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF. We compared genetic risk scores (GRS), calculated using carriage of 43 susceptibility loci for MS, in 48 cases to 1219 patients exposed to anti-TNF who did not develop demyelination. RESULTS: Overall, 39 (74%) cases were female. The median age (range) of patients at time of demyelination was 41.5 years (20.7 - 63.2). The median duration of anti-TNF treatment was 21.3 months (0.5 - 99.4) and 19 (36%) patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord or both. Complete recovery was reported in 12 (23%) patients after a median time of 6.8 months (0.1 - 28.7). After 33.0 months of follow-up partial recovery was observed in 29 (55%) patients, relapsing and remitting episodes in 9 (17%), progressive symptoms in 3 (6%): 2 (4%) patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 x 10-4, SD 0.0039) and controls (mean -1.1×10-3, SD 0.0042) (p=0.23). CONCLUSIONS: Patients who experienced demyelination events following anti-TNF were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.
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Green HD, Beaumont RN, Wood AR, Hamilton B, Jones SE, Goodhand JR, Kennedy NA, Ahmad T, Yaghootkar H, Weedon MN, et al (2020). Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study.
International Journal of Epidemiology,
49(4), 1270-1281.
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Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study
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. Background
. Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD.
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. Methods
. We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist–hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption.
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. Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference.
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. Conclusions
. These results provide strong evidence that a higher waist–hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.
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Hamilton B, Green H, Heerasing N, Hendy P, Moore L, Chanchlani N, Walker G, Bewshea C, Kennedy NA, Ahmad T, et al (2020). Incidence and prevalence of inflammatory bowel disease in Devon, UK.
Frontline GastroenterologyAbstract:
Incidence and prevalence of inflammatory bowel disease in Devon, UK
Background and aimsWe sought to define temporal changes in prevalence of inflammatory bowel disease (IBD) in East Devon, UK, in order to facilitate service planning over the next 5 years.MethodsMultiple primary and secondary care databases were used to identify and verify cases. Point prevalence and incidence of IBD were reported in April 2017 and from 2008 to 2016, respectively. Future prevalence and healthcare activity requirements were estimated by linear regression.ResultsPrevalence of ulcerative colitis (UC), Crohn’s disease (CD) and inflammatory bowel disease unclassified (IBDU) were 479.72, 265.94 and 35.34 per 100 000 persons, respectively. In 2016, the incidence rates of UC, CD and IBDU were 15.4, 10.7 and 1.4 per 100 000 persons per year, respectively. There were no significant changes in the incidence of CD (p=0.49, R=0.26) or UC (p=0.80, R=0.10). IBD prevalence has increased by 39.9% (95% CI 28.2 to 53.7) in the last 10 years without differences in the rate of change between UC and CD. Overall, 27% of patients were managed in primary care, a quarter of whom were eligible but not receiving endoscopic surveillance. Outpatient clinics, MRI and biologic use, but not helpline calls, admissions, or surgeries increased over and above the change in IBD prevalence.ConclusionsWe report one of the highest prevalence and incidence rates of IBD from Northern Europe. Overall, IBD incidence is static, but prevalence is increasing. We estimate that 1% of our population will live with IBD between 2025 and 2030.
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Walker GJ, Lin S, Chanchlani N, Thomas A, Hendy P, Heerasing N, Moore L, Green HD, Chee D, Bewshea C, et al (2020). Quality improvement project identifies factors associated with delay in IBD diagnosis. Alimentary Pharmacology & Therapeutics, 52(3), 471-480.
2019
Green HD, Beaumont RN, Thomas A, Hamilton B, Wood AR, Sharp S, Jones SE, Tyrrell J, Walker G, Goodhand J, et al (2019). Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.
J Crohns Colitis,
13(12), 1578-1582.
Abstract:
Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.
BACKGROUND AND AIMS: the causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank. METHODS: in total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores. RESULTS: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis. CONCLUSIONS: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.
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Bewshea CM, Ahmad T, Kennedy N, Goodhand J, McDonald T, Green H (2019). Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study.
Lancet Gastroenterology and Hepatology Full text.
2017
Green HD, Thomas G, Terry JR (2017). Signal reconstruction of pulmonary vein recordings using a phenomenological mathematical model: Application to pulmonary vein isolation therapy.
Frontiers in Physiology,
8(JUL).
Abstract:
Signal reconstruction of pulmonary vein recordings using a phenomenological mathematical model: Application to pulmonary vein isolation therapy
© 2017 Green, Thomas and Terry. Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is commonly initiated by ectopic beats originating from a small myocardial sleeve extending over the pulmonary veins. Pulmonary vein isolation therapy attempts to isolate the pulmonary veins from the left atrium by ablating tissue, commonly by using radiofrequency ablation. During this procedure, the cardiologist records electrical activity using a lasso catheter, and the activation pattern recorded is used as a guide toward which regions to ablate. However, poor contact between electrode and tissue can lead to important regions of electrical activity not being recorded in clinic. We reproduce these signals through the use of a phenomenological model of the cardiac action potential on a cylinder, which we fit to post-AF atrial cells, and model the bipolar electrodes of the lasso catheter by an approximation of the surface potential. The resulting activation pattern is validated by direct comparison with those of clinical recordings. A potential application of the model is to reconstruct the missing electrical activity, minimizing the impact of the information loss on the clinical procedure, and we present results to demonstrate this.
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