Publications by year
In Press
Kuo C-L, Pilling LC, Atkins JL, Kuchel GA, Melzer D (In Press). <i>ApoE</i> e2 and aging-related outcomes in 379,000 UK Biobank participants.
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ApoE e2 and aging-related outcomes in 379,000 UK Biobank participants
AbstractThe Apolipoprotein E (APOE) e4 allele is associated with reduced longevity and increased Coronary Artery Disease (CAD) and Alzheimer’s disease, with e4e4 having markedly larger effect sizes than e3e4. The e2 longevity promoting variant is less studied. We conducted a phenome-wide association study of ApoE e2e3 and e2e2 with aging phenotypes, to assess their potential as targets for anti-aging interventions. Data were from 379,000 UK Biobank participants, aged 40 to 70 years. e2e3 (n=46,535) had mostly lower lipid-related biomarker levels including reduced total and LDL-cholesterol, and lower risks of CAD (Odds Ratio=0.87, 95% CI: 0.83 to 0.90, p=4.92×10−14) and hypertension(OR=0.94, 95% CI: 0.92 to 0.97, p=7.28×10−7) versus e3e3. However, lipid changes in e2e2 (n=2,398) were more extreme, including a marked increase in triglyceride levels (0.41 Standard Deviations, 95% CI: 0.37 to 0.45, p=5.42×10−92), with no associated changes in CAD risks. There were no associations with biomarkers of kidney function. The effects of both e2e2 and e2e3 were minimal on falls, muscle mass, grip strength or frailty. In conclusion, e2e3 has protective effects on some health outcomes, but the effects of e2e2 are not similar, complicating the potential usefulness of e2 as a target for anti-aging intervention.
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Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (In Press). <i>ApoE</i> e4e4 genotype and mortality with COVID-19 in UK Biobank.
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ApoE e4e4 genotype and mortality with COVID-19 in UK Biobank
AbstractWe previously reported that the ApoE e4e4 genotype was associated with COVID-19 test positivity (OR=2.31, 95% CI: 1.65 to 3.24, p=1.19×10−6) in the UK Biobank (UKB) cohort, during the epidemic peak in England, from March 16 to April 26, 2020. With more COVID-19 test results (March 16 to May 31, 2020) and mortality data (to April 26, 2020) linked to UKB, we re-evaluated the ApoE e4 allele association with COVID-19 test positivity, and with all-cause mortality following test-confirmed COVID-19. Logistic regression models compared ApoE e4e4 participants (or e3e4s) to e3e3s with adjustment for sex; age on April 26th or age at death; baseline UKB assessment center in England (accounting for geographical differences in viral exposures); genotyping array type; and the top five genetic principal components (accounting for possible population admixture). ApoE e4e4 genotype was associated with increased risks of test positivity (OR=2.24, 95% CI: 1.72 to 2.93, p=3.24×10−9) and of mortality with test-confirmed COVID-19 (OR=4.29, 95% CI: 2.38 to 7.72, p=1.22×10−6), compared to e3e3s. Independent replications are needed to confirm our findings and mechanistic work is needed to understand how ApoE e4e4 results in the marked increase in vulnerability, especially for COVID-19 mortality. These findings also demonstrate that risks for COVID-19 mortality are not simply related to advanced chronological age or the comorbidities commonly seen in aging.
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Atkins JL, Jylhävä J, Pedersen NL, Magnusson PK, Lu Y, Wang Y, Hägg S, Melzer D, Williams DM, Pilling LC, et al (In Press). A Genome-Wide Association Study of the Frailty Index Highlights Synaptic Pathways in Aging.
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A Genome-Wide Association Study of the Frailty Index Highlights Synaptic Pathways in Aging
ABSTRACTFrailty is a common geriatric syndrome, strongly associated with disability, mortality and hospitalisation. The mechanisms underlying frailty are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 19 and 45%. Understanding the genetic determinants and biological mechanisms underpinning frailty may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) of a frailty index (FI) in European descent participants from UK Biobank (n=164,610, aged 60-70 years). FI calculation was based on 49 self-reported items on symptoms, disabilities and diagnosed diseases. We identified 26 independent genetic signals at 24 loci associated with the FI (p<5*10−8). Many of these loci have previously been associated with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, three appear to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 14% (0.14, SE 0.006). A genetic risk score for the FI, derived solely from the UK Biobank data, was significantly associated with FI in the Swedish TwinGene study (n=10,616, beta: 0.11, 95% CI: 0.02-0.20, p=0.015). In pathway analysis, genes associated with synapse function were significantly enriched (p<3*10−6). We also used Mendelian randomization to identify modifiable traits and exposures that may affect the risk of frailty, with a higher educational attainment genetic risk score being associated with a lower risk of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on synapse maintenance pathways.
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Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (In Press). ApoE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort.
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ApoE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort
The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that pre-existing dementia is a major risk factor (OR = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 hospitalization in the UK Biobank (UKB). In another UK study of 16,749 patients hospitalized for COVID-19, dementia was among the common comorbidities and was associated with higher mortality. Additionally, impaired consciousness, including delirium, is common in severe cases. The ApoE e4 genotype is associated with both dementia and delirium, with the e4e4 (homozygous) genotype associated with high risk of dementia. We therefore aimed to test associations between ApoE e4 alleles and COVID-19 severity, using the UKB data.
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Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Tignanelli C, Kuchel GA, Melzer D, Beckman KB, Levine ME, et al (In Press). COVID-19 severity is predicted by earlier evidence of accelerated aging.
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COVID-19 severity is predicted by earlier evidence of accelerated aging
AbstractWith no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2×10−6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.
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Türkmen D, Bowden J, Masoli JAH, Delgado J, Kuo C-L, Pilling LC, Melzer D (In Press). Combining pharmacogenetics and patient characteristic polygenic scores to improve outcome prediction for Calcium Channel Blocker treatment.
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Combining pharmacogenetics and patient characteristic polygenic scores to improve outcome prediction for Calcium Channel Blocker treatment
AbstractBackgroundCalcium channel blockers (CCBs) are common antihypertensive medications. Pharmacogenetic variants affect CCB clinical outcomes, although effect sizes are modest in community samples. Variation in patient characteristics may also predict CCB outcomes, and variation attributable to relevant polygenic scores is less prone to confounding. We aimed to test associations between genetically predicted patient characteristics plus pharmacogenetic variants with CCB outcomes in a large community cohort.MethodsWe extended our analysis of 32,000 UK Biobank dihydropiridine CCBs treated participants (mean duration 5.9 years) testing 23 variants, whereNUMA1rs10898815 andRYR3rs877087 showed the most robust associations (for discontinuation and heart failure, respectively). We calculated polygenic scores for systolic and diastolic blood pressures (SBP and DBP), body fat mass, waist hip ratio, lean mass, serum calcium, eGFR, lipoprotein A, urinary sodium, and liver fibrosis. Outcomes were CCB discontinuation, heart failure, coronary heart disease and chronic kidney disease.ResultsFor heart failure, the highest risk 20% of polygenic scores for fat mass, lean mass and lipoprotein a were associated with increased risks (Hazard-Ratio (HR)Fat-mass 1.46, 95% CI 1.25-1.70, p=1*10-6; HRLean-mass 1.20, 95%CI 1.04-1.38, p=0.01; HRLipoproteinA 1.29, 95% CI 1.12 to 1.48, p= 4*10-4), versus the lowest risk 20% of each score respectively. Across the cohort,RYR3T-allele modestly increased heart failure risks (HR 1.13: 1.02-1.25) versus non-carriers, but in subsets with high fat mass, lean mass, and lipoprotein a scores, estimates were substantially larger, e.g. in females aged 65-70 the heart failure Relative Risk was 4.4 (95% CI 1.54-12.4) versus no T-alleles and low scores.For CCB discontinuation, high polygenic scores for fat mass and lean mass increased risks versus the lowest 20%, whereas high SBP and DBP scores decreased discontinuation risks. Hazard ratios for discontinuation with the pharmacogenetic NUMA1 rs10898815 A-allele (overall HR 1.07: 1.02-1.12) were higher (HR 1.17: 1.05-1.29) in those with high polygenic scores for fat mass and lean mass.ConclusionPolygenic scores affecting adiposity and lipoprotein a levels add to known pharmacogenetic variants in predicting key clinical outcomes in CCB treatment. Combining pharmacogenetic variants and relevant individual characteristic polygenic scores may help for personalizing prescribing.What is needed, what do we add?We previously showed that pharmacogenetic variants inRYR3andNUMA1were associated with key clinical outcomes in community CCB patients, although effect sizes were modest. Various patient characteristics reportedly affect CCB outcomes. We therefore tested effects of relevant patient characteristics using polygenic scores. They minimize the effect of unmeasured confounders as genotypes are invariant since conception and reflect lifetime exposure to the risk factor. We showed that combining associated scores with the pharmacogenetic variants improved outcome prediction.
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Kuo C-L, Pilling LC, Liu Z, Atkins JL, Levine ME (In Press). Genetic associations for two biological age measures point to distinct aging phenotypes.
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Genetic associations for two biological age measures point to distinct aging phenotypes
AbstractBiological age measures outperform chronological age in predicting various aging outcomes, yet little is known regarding genetic predisposition. We performed genome-wide association scans of two age-adjusted biological age measures (PhenoAgeAcceleration and BioAgeAcceleration), estimated from clinical biochemistry markers1,2 in European-descent participants from UK Biobank. The strongest signals were found in the APOE gene, tagged by the two major protein-coding SNPs, PhenoAgeAccel—rs429358 (APOE e4 determinant) (p=1.50×10−72); BioAgeAccel—rs7412 (APOE e2 determinant) (p=3.16×10−60). Interestingly, we observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing the two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains. Our study reaffirms that aging patterns are heterogenous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition.
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Pilling LC, Türkmen D, Fullalove H, Atkins JL, Delgado J, Kuo C-L, Kuchel GA, Ferrucci L, Bowden J, Masoli JAH, et al (In Press). Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort.
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Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort
AbstractBackgroundThe antiplatelet drug clopidogrel is commonly prescribed for stroke and myocardial infarction (MI) prevention. Clopidogrel prodrug is predominantly activated by liver enzyme CYP2C19. CYP2C19 Loss-of-function (LoF) genetic variants have been linked to excess morbidity mainly in patients hospitalized for acute ischemic events and related interventions. Little is known about the magnitude of impact of LoF variants in family practice, especially over long periods of exposure. We aimed to determine whether CYP2C19 LoF alleles increase risk of ischemic stroke and MI in primary care patients prescribed clopidogrel for up to 18 years.MethodsRetrospective cohort analysis of 7,483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36 to 79 years at first clopidogrel prescription. We examined CYP2C19 LoF variant (*2-*8) associations with incident hospital-diagnosed ischemic stroke and MI in patients prescribed clopidogrel for at least 2 months using time-to-event models, with secondary analysis of the. 17 gain of function variant.Results28.7% (n=2,144/7,483) of included subjects (mean age 63 years at first clopidogrel prescription) carried at least one CYP2C19 intermediate or low metabolizer LoF variant. 1.9% of LoF variant carriers had an incident ischemic stroke whilst prescribed clopidogrel (mean 2.6 years, range 2 months to 18 years), versus 1.3% without the variants (0.6% absolute excess: Hazard Ratio 1.53: 95% CI 1.04 to 2.26, p=0.031). Additionally, 26.4% of CYP2C19 LoF variant carriers had an incident MI versus 24.1% (HR 1.14: 1.04 to 1.26, p=.008). Adjustment for aspirin co-prescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischemic stroke by age 79 (the oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers: the absolute excess stroke incidence with LoF variants was 7.1% by age 79.ConclusionIn family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischemic events. Genotype-guided (or routine) prescription of antiplatelet medications unaffected by CYP2C19 variants may improve outcomes in patients for whom clopidogrel is currently indicated.
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Jones G, Trajanoska K, Santanasto AJ, Stringa N, Kuo C-L, Atkins JL, Lewis JR, Duong T, Hong S, Biggs ML, et al (In Press). Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.
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Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identified 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n=48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p=4*10-17), arthritis (GDF5 p=4*10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, hematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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Melzer D, Atkins JL, Pilling LC, Heales CJ, Savage S, Kuo C-L, Kuchel GA, Steffens DC (In Press). Hemochromatosis mutations, dementia and brain iron deposition: a prospective cohort study.
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Hemochromatosis mutations, dementia and brain iron deposition: a prospective cohort study
ABSTRACTImportanceBrain iron deposition is common in dementia, but its causal significance is uncertain. The HFE p.C282Y homozygous mutation in European ancestry populations can lead to iron overload and hemochromatosis, mainly in males. Data on brain outcomes in homozygotes are scarce.ObjectiveTo estimate HFE variant associations with MRI features plus incident dementia diagnoses during follow-up in a large community based cohort.DesignUK Biobank cohort with follow-up in routine hospitalization records (mean 8.8 years). MRI imaging available on a participant subset scanned 2014 to 2018.SettingCommunity cohort participants across England, Wales and Scotland.ParticipantsEuropean ancestry participants (n=451,186) aged 40 to 70 years at baseline, including 2,890 p.C282Y homozygotes (predominantly without baseline haemochromatosis diagnoses). MRI scanning on 9,464 males and 10,475 females, including 40 male and 75 female p.C282Y homozygotes.ExposureHFE C282Y and H63D genetic variantsMain outcome and measuresBrain MRI site specific T2. measures (lower values associated with iron deposition) and gray matter volumes. Incident dementia diagnoses during follow-up.ResultsMale p.C282Y homozygotes had lower T2. measures in several brain areas including the thalamus (beta = -1.04 standard deviations, 95% CI -1.33 to -0.76, multiple testing adjusted p-value=4.9*10-10), putamen and hippocampus, compared to those without HFE mutations. Male homozygotes also had smaller gray matter volumes in the putamen (beta -0.80 sd, 95%CI -1.12 to - 0.47, adjusted p=2.2*10-4) and ventral striatum.Diagnoses of incident dementia (Hazard Ratio HR=2.27; 95% CI 1.36 to 3.80, p=0.002) were more common in p.C282Y homozygous men, as were delirium diagnoses (HR=2.04, CI 1.09 to 3.82, p=0.03), but there was no association with Stroke.In p.C282Y homozygote females and p.C282Y/H63D heterozygotes, MRI associations were less marked.Conclusion and RelevanceIn a community sample, men with the HFE p.C282Y homozygote genotype had more brain iron deposition, smaller specific gray matter volumes, and increased incidence of dementia. As iron overload in hemochromatosis is treatable, early intervention may prevent or limit related brain pathology in male HFE p.C282Y homozygotes.Key PointsQuestionIs the hemochromatosis HFE p.C282Y homozygous variant in men associated with brain MRI features and incident dementia?FindingsOn MRI, p.C282Y homozygote males had evidence of more iron deposition in areas including the thalamus, putamen and hippocampus, plus smaller putamen gray matter volumes, compared to men without HFE mutations. In 451,186 UK Biobank participants during the mean 8.8 year follow-up, incident dementia diagnoses were more than twice as common in the 1,294 homozygous men.MeaningAs iron overload in hemochromatosis is treatable, early intervention may prevent or limit related brain pathology in male HFE p.C282Y homozygotes.
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Atkins J (In Press). Hereditary hemochromatosis variant associations with incident non-liver malignancies: 11-year follow-up in UK Biobank. Cancer Epidemiology, Biomarkers and Prevention
Banfield LR, Knapp KM, Pilling LC, Melzer D, Atkins JL (In Press). Musculoskeletal outcomes with Hereditary Haemochromatosis genetic variants: 11.5 year follow-up in a community cohort.
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Musculoskeletal outcomes with Hereditary Haemochromatosis genetic variants: 11.5 year follow-up in a community cohort
AbstractBackgroundThe iron overload disorder hereditary haemochromatosis (HH) is primarily caused by the homozygousHFEp.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain.MethodsWe estimated HH-genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort. 451,143 European ancestry participants (40-70 years at baseline) were followed in hospital records (mean 11.5 years). Cox proportional hazards models estimatedHFEp.C282Y and p.H63D associations with incident outcomes.ResultsMale p.C282Y homozygotes (n=1,294) had increased incidence of osteoarthritis (n=52, HR: 2.12 [95% CI:1.61-2.80]; p=8.8*10−8), hip replacement (n=88, HR:1.84 [95% CI: 1.49-2.27]; p=1.6*10−8), knee replacement (n=61, HR:1.54 [95% CI:1.20-1.98]; p=8.4*10−4), ankle and shoulder replacement, compared to males with noHFEmutations. Lifetable estimates demonstrated 30.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 23.0% and 8.7% respectively without mutations. Male p.C282Y homozygotes also had increased incidence of femoral fractures (n=15, HR:1.72 [95% CI: 1.03-2.87]; p=0.04) and osteoporosis (n=21, HR:1.71 [95% CI: 1.11-2.64, p=0.02), although these association were limited to those with liver fibrosis/cirrhosis diagnoses. Female p.C282Y homozygotes had increased incidence of osteoarthritis only (n=57, HR:1.46, [95% CI: 1.12-1.89]; p=0.01). Male p.C282Y/p.H63D compound heterozygotes experienced a modest increased risk of hip replacements (n= 234, HR: 1.17 [95% CI: 1.02–1.33] p=0.02), but this did not pass multiple testing corrections.ConclusionsIn this large community cohort, the p.C282Y homozygote variant associated with substantial excess musculoskeletal morbidity in males. Wider iron overload orHFEgenotype testing may be justified, including in orthopaedic clinics serving higherHFEvariant prevalence populations.
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Atkins J, Masoli J, Correa-Delgado J, Pilling L, Kuo C-L, Melzer D, Kuchel G (In Press). PREEXISTING COMORBIDITIES PREDICTING COVID-19 AND MORTALITY IN THE UK BIOBANK COMMUNITY COHORT. Journal of Gerontology Series A: Biological Sciences and Medical Sciences
Atkins JL, Masoli JAH, Delgado J, Pilling LC, Kuo C-L, Kuchel GA, Melzer D (In Press). Preexisting Comorbidities Predicting Severe Covid-19 in Older Adults in the UK Biobank Community Cohort.
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Preexisting Comorbidities Predicting Severe Covid-19 in Older Adults in the UK Biobank Community Cohort
AbstractBackgroundOlder COVID-19 hospitalized patients frequently have hypertension, diabetes or coronary heart disease (CHD), but whether these are more common than in the population is unclear. During the initial epidemic in England, virus testing for older adults was restricted to symptomatic hospitalized patients. We aimed to estimate associations between pre-existing diagnoses and COVID-19 status, in a large community cohort.MethodsUK Biobank (England) participants assessed 2006 to 2010, followed in hospital discharge records to 2017. Demographic and pre-existing common diagnoses association tested with COVID-19 status (16th March to 14th April 2020) in logistic models, adjusted for demographics, study site and other diagnoses.ResultsThere were 274,356 participants aged 65+, including 448 (0.16%) hospitalized COVID-19 patients. Common co-morbidities in patients were hypertension (58.5%), coronary heart disease (CHD, 21.1%), history of fall or fragility fractures (30.6%), and type 2 diabetes (19.6%). However, in adjusted models, COVID-19 patients were more likely than other participants to have pre-existing dementia (OR=3.07 95% CI 1.71 to 5.50), COPD (OR= 1.82 CI 1.33 to 2.49), depression (OR=1.81 CI 1.36 to 2.40), type 2 diabetes (OR=1.70 CI 1.30 to 2.21), chronic kidney disease and atrial fibrillation. Hypertension was modestly associated (OR=1.29 CI 1.04 to 1.59), but CHD (OR=0.92 CI 0.71 to 1.20) prevalence was similar in COVID-19 patients and other participants.ConclusionSpecific co-morbidities are disproportionally common in older adults who develop severe COVID-19. Tailored interventions may be needed, as these results do not support simple age-based targeting to prevent severe COVID-19 infection.
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Türkmen D, Masoli JAH, Kuo C-L, Bowden J, Melzer D, Pilling LC (In Press). Statin treatment effectiveness and the <i>SLCO1B1</i>*5 reduced function genotype: long-term outcomes in women and men.
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Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: long-term outcomes in women and men
ABSTRACTObjectiveTo estimate the effect of the SLCO1B1*5 genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications.Methods and Analysis69,185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40 to 79 years at first prescription; treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5mmol/L) at baseline, plus treatment discontinuation.Results48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol, vs. 41.7% of those with functioning SLCO1B1 (Odds Ratio 1.31: 95% Confidence Intervals 1.1 to 1.55, p=0.001). Fewer males had high cholesterol, and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (Hazard Ratio 1.19: 95%CI 1.03 to 1.37, p=0.01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3: 95%CI 1.08 to 1.56; p=0.006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year.ConclusionsIn this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.What is already known about this subjectGenetic variants affecting SLCO1B1 (statin transporter) gene function increase concentrations of unmetabolized statin molecules (mostly simvastatin and atorvastatin). Previous studies of statin-treated patients have reported reduced likelihood of achieving target cholesterol levels plus increased adverse effects and medication non-adherence mainly in the first year of treatment.However, little data have been available on key outcomes over longer follow-ups or on outcomes by sex, despite large differences in statin treatment patterns between men and women.What this study addsIn 69,185 UK Biobank participants reporting simvastatin or atorvastatin use at baseline assessment, substantially more women had clinically high total cholesterol (>5 mmol/L) compared to men (42% vs. 25%). Female carriers of the SLCO1B1*5 (decreased SLCO1B1 function) genetic variant were especially likely to have high cholesterol, despite being on statin treatment.In primary care records of atorvastatin and simvastatin prescribing (>10 years follow-up), female carriers of SLCO1B1*5 were more likely to stop statins. In men, SLCO1B1*5 was only associated with discontinuing statin treatment in the first year after starting treatment.
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Bowden J, Pilling LC, Türkmen D, Kuo C-L, Melzer D (In Press). The Triangulation WIthin a STudy (TWIST) framework for causal inference within Pharmacogenetic research.
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The Triangulation WIthin a STudy (TWIST) framework for causal inference within Pharmacogenetic research
AbstractIn this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework ‘Triangulation WIthin a STudy’ (TWIST)’ in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.
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Kuo C-L, Kirk B, Xiang M, Pilling LC, Kuchel GA, Kremer R, Duque G (In Press). Very Low and High Levels of Vitamin D are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants.
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Very Low and High Levels of Vitamin D are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants
Background: Shorter leukocyte telomere length (LTL) is observed in multiple age-related diseases, which are also associated with vitamin D deficiency (i.e. osteosarcopenia, neurocognitive disorders, cancer, osteoarthritis, etc.), which suggests a close association. In this study, we examined the relationship between vitamin D levels and LTL in older participants of the UK Biobank. Methods: Data were collected from the UK Biobank. Participants aged 60 and older (n=148,321) were included. Baseline LTL was measured using a multiplex qPCR technique and expressed as the ratio of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Se-rum 25-hydroxyvitamin D (25OHD) was stratified by z score and linked to LTL in a linear regression model adjusting for covariates. Results: Compared to the medium level, a low (in the range of 16.6 nmol/L, 29.7 nmol/L) or extremely low (&le; 16.6 nmol/L) level of serum 25OHD was associated with shorter LTL: 0.018 SD (standardized &beta;= -0.018, 95% CI -0.033 to -0.003, P=0.022) and 0.048 SD (standardized &beta;= -0.048, 95% CI -0.083 to -0.014, P=0.006), respectively. Additionally, the high serum 25OHD groups (&gt; 95.9 nmol/L) had 0.038 SD (standardized &beta;= -0.038, 95% CI -0.072 to -0.004, P=0.030) shorter mean LTL than the group with medium 25OHD levels. The associations above were adjusted for multiple variables. Conclusion: in this population-based study, we identified an inverted U-shape relationship between LTL and vitamin D status. Whether high or low vitamin D-associated shorter LTL is mechanistically related to age-related conditions remains to be elucidated.
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2022
Kuo C-L, Pilling LC, Atkins JL, Fortinsky RH, Kuchel GA, Melzer D (2022). APOE e4 Genotypes Increase Risk of Delirium During COVID-19-Related Hospitalizations: Evidence from a Large UK Cohort.
J Gerontol a Biol Sci Med Sci,
77(4), 879-880.
Author URL.
Pilling LC, Atkins JL, Melzer D (2022). Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.
Hepatology,
76(6), 1735-1745.
Abstract:
Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.
BACKGROUND: the iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers. METHODS: We studied 1294 male and 1596 female UK Biobank HFE p.C282Y homozygous participants of European ancestry with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups. RESULTS: in male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20% = 4.90: 95% confidence intervals, 1.63-14.73; p = 0.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y/p.H63D genotypes. CONCLUSIONS: HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.
Abstract.
Author URL.
Masoli JAH, Pilling LC, Frayling TM (2022). Genomics and multimorbidity.
Age and Ageing,
51(12).
Abstract:
Genomics and multimorbidity
Abstract
. Multimorbidity has increased in prevalence world-wide. It is anticipated to affect over 1 in 6 of the UK population by 2035 and is now recognised as a global priority for health research. Genomic medicine has rapidly advanced over the last 20 years from the first sequencing of the human genome to integration into clinical care for rarer conditions. Genetic studies help identify new disease mechanisms as they are less susceptible to the bias and confounding that affects epidemiological studies, as genetics are assigned from conception. There is also genetic variation in the efficacy of medications and the risk of side effects, pharmacogenetics. Genomic approaches offer the potential to improve our understanding of mechanisms underpinning multiple long-term conditions/multimorbidity and guide precision approaches to risk, diagnosis and optimisation of management. In this commentary as part of the Age and Ageing 50th anniversary commentary series, we summarise genomics and the potential utility of genomics in multimorbidity.
Abstract.
Gautvik KM, Olstad OK, Raue U, Gautvik VT, Kvernevik KJ, Utheim TP, Ravnum S, Kirkegaard C, Wiig H, Jones G, et al (2022). Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults.
EUROPEAN REVIEW OF AGING AND PHYSICAL ACTIVITY,
19(1).
Author URL.
Türkmen D, Masoli JAH, Kuo C, Bowden J, Melzer D, Pilling LC (2022). Statin treatment effectiveness and the. <i>SLCO1B1</i>. 5 reduced function genotype: Long‐term outcomes in women and men. British Journal of Clinical Pharmacology, 88(7), 3230-3240.
2021
Atkins JL, Jylhävä J, Pedersen NL, Magnusson PK, Lu Y, Wang Y, Hägg S, Melzer D, Williams DM, Pilling LC, et al (2021). A genome-wide association study of the frailty index highlights brain pathways in ageing.
Aging Cell,
20(9).
Abstract:
A genome-wide association study of the frailty index highlights brain pathways in ageing.
Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60-70 years) and Swedish TwinGene participants (n = 10,616, 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p
Abstract.
Author URL.
Pilling LC, Turkmen D, Fullalove H, Atkins JL, Delgado J, Kuo C-L, Kuchel GA, Ferrucci L, Bowden J, Masoli JAH, et al (2021). Analysis of CYP2C19 genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study.
BMJ OPEN,
11(12).
Author URL.
Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Tignanelli C, Kuchel GA, Melzer D, Beckman KB, Levine ME, et al (2021). Biological Aging Predicts Vulnerability to COVID-19 Severity in UK Biobank Participants.
The Journals of Gerontology: Series A,
76(8), e133-e141.
Abstract:
Biological Aging Predicts Vulnerability to COVID-19 Severity in UK Biobank Participants
Abstract
.
. Background
. Age and disease prevalence are the 2 biggest risk factors for Coronavirus disease 2019 (COVID-19) symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity.
.
.
. Methods
. Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of 2 COVID-19 severity outcomes (inpatient test positivity and COVID-19-related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and preexisting diseases/conditions.
.
.
. Results
. Six hundred and thirteen participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19-related mortality (ORMortality = 1.63 per 5 years, 95% CI: 1.43–1.86, p = 4.7 × 10−13) adjusting for demographics including age at the pandemic. Further adjustment for preexisting diseases/conditions at baseline (ORM = 1.50, 95% CI: 1.30–1.73 per 5 years, p = 3.1 × 10−8) and at the early pandemic (ORM = 1.21, 95% CI: 1.04–1.40 per 5 years, p =. 011) decreased the association.
.
.
. Conclusions
. PhenoAge measured in 2006–2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions.
.
Abstract.
Kuo C-L, Pilling LC, Liu Z, Atkins JL, Levine ME (2021). Genetic associations for two biological age measures point to distinct aging phenotypes.
Aging Cell,
20(6).
Abstract:
Genetic associations for two biological age measures point to distinct aging phenotypes.
Biological age measures outperform chronological age in predicting various aging outcomes, yet little is known regarding genetic predisposition. We performed genome-wide association scans of two age-adjusted biological age measures (PhenoAgeAcceleration and BioAgeAcceleration), estimated from clinical biochemistry markers (Levine et al. 2018; Levine, 2013) in European-descent participants from UK Biobank. The strongest signals were found in the APOE gene, tagged by the two major protein-coding SNPs, PhenoAgeAccel-rs429358 (APOE e4 determinant) (p = 1.50 × 10-72 ); BioAgeAccel-rs7412 (APOE e2 determinant) (p = 3.16 × 10-60 ). Interestingly, we observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing the two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains. Our study reaffirms that aging patterns are heterogeneous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition.
Abstract.
Author URL.
Jones G, Trajanoska K, Santanasto AJ, Stringa N, Kuo C-L, Atkins JL, Lewis JR, Duong T, Hong S, Biggs ML, et al (2021). Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.
Nature Communications,
12(1).
Abstract:
Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
AbstractLow muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
Abstract.
Atkins JL, Pilling LC, Heales CJ, Savage S, Kuo C-L, Kuchel GA, Steffens DC, Melzer D (2021). Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort.
Journal of Alzheimer's Disease,
79(3), 1203-1211.
Abstract:
Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort
Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: to estimate p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2. measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2. measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.
Abstract.
Bowden J, Pilling LC, Türkmen D, Kuo C-L, Melzer D (2021). The Triangulation WIthin a STudy (TWIST) framework for causal inference within pharmacogenetic research.
PLOS Genetics,
17(9), e1009783-e1009783.
Abstract:
The Triangulation WIthin a STudy (TWIST) framework for causal inference within pharmacogenetic research
In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework ‘Triangulation WIthin a STudy’ (TWIST)’ in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.
Abstract.
2020
Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (2020). APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort.
J Gerontol a Biol Sci Med Sci,
75(11), 2231-2232.
Author URL.
Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (2020). ApoE e4e4 Genotype and Mortality with COVID-19 in UK Biobank. The Journals of Gerontology: Series A, 75(9), 1801-1803.
Atkins JL, Pilling LC, Masoli JAH, Kuo C-L, Shearman JD, Adams PC, Melzer D (2020). Association of Hemochromatosis <i>HFE</i> p.C282Y Homozygosity with Hepatic Malignancy. JAMA, 324(20), 2048-2048.
Colicino E, Marioni R, Ward-Caviness C, Gondalia R, Guan W, Chen B, Tsai P-C, Huan T, Xu G, Golareh A, et al (2020). Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.
Aging (Albany NY),
12(14), 14092-14124.
Abstract:
Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.
DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
Abstract.
Author URL.
Masoli JAH, Delgado J, Pilling L, Strain D, Melzer D (2020). Blood pressure in frail older adults: associations with cardiovascular outcomes and all-cause mortality.
Age Ageing,
49(5), 807-813.
Abstract:
Blood pressure in frail older adults: associations with cardiovascular outcomes and all-cause mortality.
BACKGROUND: Blood pressure (BP) management in frail older people is challenging. An randomised controlled trial of largely non-frail older people found cardiovascular and mortality benefit with systolic (S) BP target 150 mmHg. Associations with mortality varied between non-frail
Abstract.
Author URL.
Pilling LC, Jones LC, Masoli JAH, Delgado J, Atkins JL, Bowden J, Fortinsky RH, Kuchel GA, Melzer D (2020). Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older. <scp>UK</scp>. Biobank Participants. Journal of the American Geriatrics Society, 69(2), 365-372.
Jones G, Pilling LC, Kuo C-L, Kuchel G, Ferrucci L, Melzer D (2020). Sarcopenia and Variation in the Human Leukocyte Antigen Complex.
J Gerontol a Biol Sci Med Sci,
75(2), 301-308.
Abstract:
Sarcopenia and Variation in the Human Leukocyte Antigen Complex.
BACKGROUND: Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. METHODS: Data were collected from 181,301 UK Biobank European descent volunteers aged 60-70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. RESULTS: Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74-1.92, p = 4.0*10-125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p = 2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12-1.35, p = 7.28*10-6). of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05-1.11, p = 1.06*10-8 and 1.07, CI 1.04-1.09, p = 1.5*10-6, respectively). Some HLA associations with sarcopenia were greater in female participants. CONCLUSION: Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.
Abstract.
Author URL.
Kuo C-L, Joaquim M, Kuchel GA, Ferrucci L, Harries LW, Pilling LC, Melzer D (2020). The Longevity-Associated SH2B3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects.
J Gerontol a Biol Sci Med Sci,
75(9), 1656-1662.
Abstract:
The Longevity-Associated SH2B3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects.
Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal, and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were obtained from 379,758 European-descent UK Biobank participants, aged 40-70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers aged ≥96 years) was more common in CC versus TT (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR = 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR = 1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target.
Abstract.
Author URL.
Tian Q, Pilling LC, Atkins JL, Melzer D, Ferrucci L (2020). The relationship of parental longevity with the aging brain—results from UK Biobank.
GeroScience,
42(5), 1377-1385.
Abstract:
The relationship of parental longevity with the aging brain—results from UK Biobank
A few studies report that parental longevity is associated with preserved cognition and physical function and lower risk of Alzheimer’s disease. However, data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain structure and to explore sex differences. We identified 12,970 UK Biobank participants (mean age = 64.4, 51.5%women) with data on parental longevity, regional gray matter volumes, and white matter microstructure. Participants were categorized based on whether at least one parent lived to age 85 or older or neither parent survived to age 85. Associations of parental longevity, maternal, and paternal longevity with each neuroimaging marker of interest were examined using linear regression, adjusted for demographics, APOE e4 status, lifestyle, and cardiometabolic conditions. Compared to participants whose both parents died before 85 (43%), those with at least one parent surviving to 85 (57%) had greater volumes in hippocampus, parahippocampal gyrus, middle temporal lobe, and primary sensorimotor cortex and had lower mean diffusivity in posterior thalamic radiation and uncinate fasciculus. Associations were prominent with maternal longevity. Adjustment for cardiometabolic conditions did not affect observed associations except mean diffusivity in posterior thalamic radiation. There were no structural differences in other areas. Parental longevity is associated with preserved brain structure localized in primary sensorimotor cortex and temporal areas including hippocampus. These relationships are prominent with maternal longevity. Longitudinal studies are needed to determine whether changes in these brain structures account for the association between parental longevity and dementia.
Abstract.
Haque S, Ames RM, Moore K, Pilling LC, Peters LL, Bandinelli S, Ferrucci L, Harries LW (2020). circRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan.
Geroscience,
42(1), 183-199.
Abstract:
circRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan.
Circular RNAs (circRNAs) are an emerging class of non-coding RNA molecules that are thought to regulate gene expression and human disease. Despite the observation that circRNAs are known to accumulate in older organisms and have been reported in cellular senescence, their role in aging remains relatively unexplored. Here, we have assessed circRNA expression in aging human blood and followed up age-associated circRNA in relation to human aging phenotypes, mammalian longevity as measured by mouse median strain lifespan and cellular senescence in four different primary human cell types. We found that circRNAs circDEF6, circEP300, circFOXO3 and circFNDC3B demonstrate associations with parental longevity or hand grip strength in 306 subjects from the InCHIANTI study of aging, and furthermore, circFOXO3 and circEP300 also demonstrate differential expression in one or more human senescent cell types. Finally, four circRNAs tested showed evidence of conservation in mouse. Expression levels of one of these, circPlekhm1, was nominally associated with lifespan. These data suggest that circRNA may represent a novel class of regulatory RNA involved in the determination of aging phenotypes, which may show future promise as both biomarkers and future therapeutic targets for age-related disease.
Abstract.
Author URL.
2019
Agha G, Mendelson MM, Ward-Caviness CK, Joehanes R, Huan T, Gondalia R, Salfati E, Brody JA, Fiorito G, Bressler J, et al (2019). Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.
Circulation,
140(8), 645-657.
Abstract:
Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.
BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate
Abstract.
Author URL.
Pilling L, Tamosauskaite J, Jones G, Wood A, Jones L, Kuo C-L, Kuchel G, Ferrucci L, Melzer D (2019). Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ
Tamosauskaite J, Atkins J, Pilling L, Kuo C-L, Kuchel G, Ferrucci L, Melzer D (2019). Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain: Evidence from 200,975 Older UK Biobank Participants. Journals of Gerontology - Series a Biological Sciences and Medical Sciences
Kuo C-L, Pilling LC, Kuchel GA, Ferrucci L, Melzer D (2019). Telomere length and aging-related outcomes in humans: a Mendelian randomization study in 261,000 older participants.
Aging Cell,
18(6).
Abstract:
Telomere length and aging-related outcomes in humans: a Mendelian randomization study in 261,000 older participants.
Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks.
Abstract.
Author URL.
Melzer D, Pilling LC, Ferrucci L (2019). The genetics of human ageing. Nature Reviews Genetics, 21(2), 88-101.
Lee BP, Pilling LC, Bandinelli S, Ferrucci L, Melzer D, Harries LW (2019). The transcript expression levels of HNRNPM, HNRNPA0 and AKAP17A splicing factors may be predictively associated with ageing phenotypes in human peripheral blood.
Biogerontology,
20(5), 649-663.
Abstract:
The transcript expression levels of HNRNPM, HNRNPA0 and AKAP17A splicing factors may be predictively associated with ageing phenotypes in human peripheral blood.
Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in peripheral blood samples from the InCHIANTI Study of Aging, and assessed longitudinal relationships with human ageing phenotypes (cognitive decline and physical ability) using multivariate linear regression. AKAP17A, HNRNPA0 and HNRNPM transcript levels were all predictively associated with severe decline in MMSE score (p = 0.007, 0.001 and 0.008 respectively). Further analyses also found expression of these genes was associated with a performance decline in two other cognitive measures; the Trail Making Test and the Purdue Pegboard Test. AKAP17A was nominally associated with a decline in mean hand-grip strength (p = 0.023), and further analyses found nominal associations with two other physical ability measures; the Epidemiologic Studies of the Elderly-Short Physical Performance Battery and calculated speed (m/s) during a timed 400 m fast walking test. These data add weight to the hypothesis that splicing dyregulation may contribute to the development of some ageing phenotypes in the human population.
Abstract.
Author URL.
Bowman K, Jones L, Pilling LC, Delgado J, Kuchel GA, Ferrucci L, Fortinsky RH, Melzer D (2019). Vitamin D levels and risk of delirium: a mendelian randomization study in the UK Biobank. Neurology
2018
Pilling LC, Masoli J, Melzer D, Kuchel G (2018). Clinical Outcomes of CADASIL-Associated NOTCH3 Mutations in 451,424 European Ancestry Community Volunteers. Translational Stroke Research
Atkins JL, Delgado J, Pilling L, Bowman K, Masoli J, Kuchel G, Ferrucci L, Melzer D (2018). Impact of Low Cardiovascular Risk Profiles on Geriatric Outcomes: Evidence from 421,000 Participants in Two Cohorts. Journals of Gerontology: Medical Sciences
Pilling LC, Atkins JL, Kuchel GA, Ferrucci L, Melzer D (2018). Red cell distribution width and common disease onsets in 240,477 healthy volunteers followed for up to 9 years.
PLoS ONE,
13(9).
Abstract:
Red cell distribution width and common disease onsets in 240,477 healthy volunteers followed for up to 9 years
Higher Red Blood Cell Distribution Width (RDW or anisocytosis) predicts incident coronary artery disease (CAD) plus all-cause and cardiovascular mortality, but its predictive value for other common diseases in healthy volunteers is less clear. We aimed to determine the shorter and longer term associations between RDW and incident common conditions in participants free of baseline disease, followed for 9 years. We undertook a prospective analysis of RDW% using 240,477 healthy UK Biobank study volunteers aged 40–70 years at baseline, with outcomes ascertained during follow-up (9 years). Participants were free of anemia, CAD, type-2 diabetes, stroke, hypertension, COPD, and any cancer (except non-melanoma skin cancer) at baseline. Survival models (with competing Hazards) tested associations with outcomes from hospital admission records and death certificates. High RDW (15% variation, n = 6,050) compared to low (
Abstract.
Latorre E, Pilling LC, Lee BP, Bandinelli S, Melzer D, Ferrucci L, Harries LW (2018). The VEGFA156b isoform is dysregulated in senescent endothelial cells and may be associated with prevalent and incident coronary heart disease.
Clin Sci (Lond),
132(3), 313-325.
Abstract:
The VEGFA156b isoform is dysregulated in senescent endothelial cells and may be associated with prevalent and incident coronary heart disease.
Coronary heart disease (CHD) is a leading cause of morbidity in people over 65 years of age; >40% of all deaths are due to this condition. The association between increasing age and CHD is well documented; the accumulation of senescent cells in cardiac and vascular tissues may represent one factor underpinning this observation. We aimed to identify senescence-related expression changes in primary human senescent cardiomyocytes and endothelial cells and to relate transcript expression in peripheral blood leucocytes to prevalent and incident CHD in the InCHIANTI study of aging. We quantified splicing factor expression and splicing patterns of candidate transcripts in proliferative and senescent later passage endothelial cells and cardiomyocytes using qRTPCR. Senescence-associated isoforms also expressed in peripheral blood leucocytes were then examined for associations with CHD status in 134 pairs of age, sex and BMI-matched CHD cases and controls. Splicing factor expression was dysregulated in senescent cardiomyocytes, as previously reported for endothelial cells, as was the expression of alternatively expressed cardiac and vascular candidate genes in both cell types. We found nominal associations between the expression of VEGFA156b and FNI-EIIIIA isoforms in peripheral blood mRNA and CHD status. Dysregulated splicing factor expression is a key feature of senescent cardiomyocytes and endothelial cells. Altered splicing of key cardiac or endothelial genes may contribute to the risk of CHD in the human population.
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Author URL.
2017
Tanaka T, Dutta A, Pilling LC, Xue L, Lunetta KL, Murabito JM, Bandinelli S, Wallace R, Melzer D, Ferrucci L, et al (2017). Genome-wide Association Study of Parental Life Span.
J Gerontol a Biol Sci Med Sci,
72(10), 1407-1410.
Abstract:
Genome-wide Association Study of Parental Life Span.
BACKGROUND: Having longer lived parents has been shown to be an important predictor of health trajectories and life span. As such, parental life span is an important phenotype that may uncover genes that affect longevity. METHODS: a genome-wide association study of parental life span in participants of European and African ancestry from the Health and Retirement Study was conducted. RESULTS: a genome-wide significant association was observed for rs35715456 (log10BF = 6.3) on chromosome 18 for the dichotomous trait of having at least one long-lived parent versus not having any long-lived parent. This association was not replicated in an independent sample from the InCHIANTI and Framingham Heart Study. The most significant association among single nucleotide polymorphisms in longevity candidate genes (APOE, MINIPP1, FOXO3, EBF1, CAMKIV, and OTOL1) was observed in the EBF1 gene region (rs17056207, p =. 0002). CONCLUSIONS: a promising genetic signal for parental life span was identified but was not replicated in independent samples.
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Author URL.
Pilling LC, Kuo C-L, Sicinski K, Tamosauskaite J, Kuchel GA, Harries LW, Herd P, Wallace R, Ferrucci L, Melzer D, et al (2017). Human longevity: 25 genetic loci associated in 389,166 UK biobank participants.
Aging (Albany NY),
9(12), 2504-2520.
Abstract:
Human longevity: 25 genetic loci associated in 389,166 UK biobank participants.
We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p
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Author URL.
Pilling LC, Atkins JL, Duff MO, Beaumont RN, Jones SE, Tyrrell J, Kuo C-L, Ruth KS, Tuke MA, Yaghootkar H, et al (2017). Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.
PLoS One,
12(9).
Abstract:
Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.
INTRODUCTION: Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. RESULTS: a large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%,
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Author URL.
2016
Huan T, Joehanes R, Schurmann C, Schramm K, Pilling LC, Peters MJ, Mägi R, DeMeo D, O'Connor GT, Ferrucci L, et al (2016). A whole-blood transcriptome meta-analysis identifies gene expression signatures of cigarette smoking.
Human Molecular Genetics,
25(21), 4611-4623.
Abstract:
A whole-blood transcriptome meta-analysis identifies gene expression signatures of cigarette smoking
Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a metaanalysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR) < 0.1, we identified 1270 differentially expressed genes in current vs. never smokers, and 39 genes in former vs. never smokers. Expression levels of 12 genes remained elevated up to 30 years after smoking cessation, suggesting that the molecular consequence of smoking may persist for decades. Gene ontology analysis revealed enrichment of smoking-related genes for activation of platelets and lymphocytes, immune response, and apoptosis. Many of the top smoking-related differentially expressed genes, including LRRN3 and GPR15, have DNA methylation loci in promoter regions that were recently reported to be hypomethylated among smokers. By linking differential gene expression with smoking-related disease phenotypes, we demonstrated that stroke and pulmonary function show enrichment for smoking-related gene expression signatures. Mediation analysis revealed the expression of several genes (e.g. ALAS2) to be putative mediators of the associations between smoking and inflammatory biomarkers (IL6 and C-reactive protein levels). Our transcriptomic study provides potential insights into the effects of cigarette smoking on gene expression in whole blood and their relations to smoking-related diseases. The results of such analyses may highlight attractive targets for treating or preventing smoking-related health effects.
Abstract.
Huan T, Joehanes R, Schurmann C, Schramm K, Pilling LC, Peters MJ, Mägi R, DeMeo D, O'Connor GT, Ferrucci L, et al (2016). A whole-blood transcriptome meta-analysis identifies gene expression signatures of cigarette smoking.
Hum Mol Genet,
25(21), 4611-4623.
Abstract:
A whole-blood transcriptome meta-analysis identifies gene expression signatures of cigarette smoking.
Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR)
Abstract.
Author URL.
Moore AZ, Hernandez DG, Tanaka T, Pilling LC, Nalls MA, Bandinelli S, Singleton AB, Ferrucci L (2016). Change in Epigenome-Wide DNA Methylation over 9 Years and Subsequent Mortality: Results from the InCHIANTI Study.
J Gerontol a Biol Sci Med Sci,
71(8), 1029-1035.
Abstract:
Change in Epigenome-Wide DNA Methylation over 9 Years and Subsequent Mortality: Results from the InCHIANTI Study.
Patterns of DNA methylation (DNAm) that track with aging have been identified. However, the relevance of these patterns for aging outcomes remains unclear. Longitudinal epigenome-wide DNAm information was obtained from the InCHIANTI study, a large representative European population. DNAm was evaluated using the Illumina HumanMethylation450 array on blood samples collected at baseline and 9-year follow-up: observations from 499 participants with paired longitudinal blood sample and information on differential blood count were included in analyses. A total of 56,579 markers were significantly associated with age in cross-sectional analysis of DNAm at year 9, 31,252 markers were changed significantly over the 9-year follow-up, and 16,987 markers were both cross-sectionally associated with age and significantly changed over time. Rates of change at 76 markers and year 9 level of DNAm at 88 markers were identified as strongly associated with mortality in Cox proportional hazard models adjusted for age and relevant covariates (mean follow-up time 4.4 years). Less than 0.05% of markers associated with age or that changed over time were also associated with mortality after adjusting for chronological age. Although the influence of DNAm on health and longevity remains unclear, these findings confirm that aging is associated cross-sectionally and longitudinally with robust and consistent patterns of methylation change.
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Author URL.
Lee BP, Pilling LC, Emond F, Flurkey K, Harrison DE, Yuan R, Peters LL, Kuchel GA, Ferrucci L, Melzer D, et al (2016). Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans.
Aging Cell,
15(5), 903-913.
Abstract:
Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans.
Dysregulation of splicing factor expression and altered alternative splicing are associated with aging in humans and other species, and also with replicative senescence in cultured cells. Here, we assess whether expression changes of key splicing regulator genes and consequent effects on alternative splicing are also associated with strain longevity in old and young mice, across 6 different mouse strains with varying lifespan (A/J, NOD.B10Sn-H2(b) /J, PWD.Phj, 129S1/SvlmJ, C57BL/6J and WSB/EiJ). Splicing factor expression and changes to alternative splicing were associated with strain lifespan in spleen and to a lesser extent in muscle. These changes mainly involved hnRNP splicing inhibitor transcripts with most changes more marked in spleens of young animals from long-lived strains. Changes in spleen isoform expression were suggestive of reduced cellular senescence and retained cellular proliferative capacity in long-lived strains. Changes in muscle isoform expression were consistent with reduced pro-inflammatory signalling in longer-lived strains. Two splicing regulators, HNRNPA1 and HNRNPA2B1, were also associated with parental longevity in humans, in the InCHIANTI aging study. Splicing factors may represent a driver, mediator or early marker of lifespan in mouse, as expression differences were present in the young animals of long-lived strains. Changes to alternative splicing patterns of key senescence genes in spleen and key remodelling genes in muscle suggest that correct regulation of alternative splicing may enhance lifespan in mice. Expression of some splicing factors in humans was also associated with parental longevity, suggesting that splicing regulation may also influence lifespan in humans.
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Ligthart S, Marzi C, Aslibekyan S, Mendelson MM, Conneely KN, Tanaka T, Colicino E, Waite LL, Joehanes R, Guan W, et al (2016). DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.
Genome Biol,
17(1).
Abstract:
DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.
BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P
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Author URL.
Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai P-C, Roetker NS, Just AC, Demerath EW, Guan W, et al (2016). DNA methylation-based measures of biological age: meta-analysis predicting time to death.
Aging (Albany NY),
8(9), 1844-1865.
Abstract:
DNA methylation-based measures of biological age: meta-analysis predicting time to death.
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p
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Author URL.
Joehanes R, Just AC, Marioni RE, Pilling LC, Reynolds LM, Mandaviya PR, Guan W, Xu T, Elks CE, Aslibekyan S, et al (2016). Epigenetic Signatures of Cigarette Smoking.
Circ Cardiovasc Genet,
9(5), 436-447.
Abstract:
Epigenetic Signatures of Cigarette Smoking.
BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. METHODS AND RESULTS: to comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P
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Ibrahim-Verbaas CA, Bressler J, Debette S, Schuur M, Smith AV, Bis JC, Davies G, Trompet S, Smith JA, Wolf C, et al (2016). GWAS for executive function and processing speed suggests involvement of the CADM2 gene.
Mol Psychiatry,
21(2), 189-197.
Abstract:
GWAS for executive function and processing speed suggests involvement of the CADM2 gene.
To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts a and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
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Author URL.
Pilling LC, Joehanes R, Kacprowski T, Peters M, Jansen R, Karasik D, Kiel DP, Harries LW, Teumer A, Powell J, et al (2016). Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.
Physiol Genomics,
48(1), 1-11.
Abstract:
Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.
Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (
Abstract.
Author URL.
Pilling LC, Atkins JL, Bowman K, Jones SE, Tyrrell J, Beaumont RN, Ruth KS, Tuke MA, Yaghootkar H, Wood AR, et al (2016). Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
Aging (Albany NY),
8(3), 547-560.
Abstract:
Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.
Abstract.
Author URL.
Atkins JL, Pilling LC, Ble A, Dutta A, Harries LW, Murray A, Brayne C, Robine J-M, Kuchel GA, Ferrucci L, et al (2016). Longer-Lived Parents and Cardiovascular Outcomes: 8-Year Follow-Up in 186,000 U.K. Biobank Participants.
J Am Coll Cardiol,
68(8), 874-875.
Author URL.
Chen BH, Hivert M-F, Peters MJ, Pilling LC, Hogan JD, Pham LM, Harries LW, Fox CS, Bandinelli S, Dehghan A, et al (2016). Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations.
Diabetes,
65(12), 3794-3804.
Abstract:
Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations.
Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q
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Author URL.
Demirkan A, Lahti J, Direk N, Viktorin A, Lunetta KL, Terracciano A, Nalls MA, Tanaka T, Hek K, Fornage M, et al (2016). Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.
Psychol Med,
46(8), 1613-1623.
Abstract:
Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.
BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
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Author URL.
2015
Huan T, Esko T, Peters MJ, Pilling LC, Schramm K, Schurmann C, Chen BH, Liu C, Joehanes R, Johnson AD, et al (2015). A meta-analysis of gene expression signatures of blood pressure and hypertension.
PLoS Genet,
11(3).
Abstract:
A meta-analysis of gene expression signatures of blood pressure and hypertension.
Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p
Abstract.
Author URL.
Blackwell J, Harries LW, Pilling LC, Ferrucci L, Jones A, Melzer D (2015). Changes in CEBPB expression in circulating leukocytes following eccentric elbow-flexion exercise.
Journal of Physiological Sciences,
65(1), 145-150.
Abstract:
Changes in CEBPB expression in circulating leukocytes following eccentric elbow-flexion exercise
In mouse models, CCAAT enhancer-binding protein beta (CEBPB) is necessary for M2 macrophage-mediated regeneration after muscle injury. In humans, CEBPB expression in blood was strongly associated with muscle strength. In this study we aimed to test whether CEBPB expression in blood in people is increased 2 days after exercise designed to induce muscle damage and subsequent repair. Sixteen healthy male volunteers undertook elbow flexor exercises designed to induce acute muscle micro-damage. Peripheral blood samples were collected at baseline and days 1, 2, 4 and 7 following exercise. Expression of CEBPB and related genes were analysed by qRT-PCR. Extent of muscle damage was determined by decline in maximal voluntary isometric torque and by plasma creatine kinase activity. Nine subjects had peak (day 4) creatine kinase activity exceeding 10,000 U/l. In this subgroup, CEBPB expression was elevated from baseline to 2 days post exercise (paired-samples t(1,8) = 3.72, p = 0.006). Related expression and selected cytokine changes after exercise did not reach significance. Muscle-damaging exercise in humans can be followed by induction of CEBPB transcript expression in peripheral blood. Associations between CEBPB expression in blood and muscle strength may be consistent with the CEBPB-dependent muscle repair process.
Abstract.
Blackwell J, Harries LW, Pilling LC, Ferrucci L, Jones A, Melzer D (2015). Changes in CEBPB expression in circulating leukocytes following eccentric elbow-flexion exercise.
J Physiol Sci,
65(1), 145-150.
Abstract:
Changes in CEBPB expression in circulating leukocytes following eccentric elbow-flexion exercise.
In mouse models, CCAAT enhancer-binding protein beta (CEBPB) is necessary for M2 macrophage-mediated regeneration after muscle injury. In humans, CEBPB expression in blood was strongly associated with muscle strength. In this study we aimed to test whether CEBPB expression in blood in people is increased 2 days after exercise designed to induce muscle damage and subsequent repair. Sixteen healthy male volunteers undertook elbow flexor exercises designed to induce acute muscle micro-damage. Peripheral blood samples were collected at baseline and days 1, 2, 4 and 7 following exercise. Expression of CEBPB and related genes were analysed by qRT-PCR. Extent of muscle damage was determined by decline in maximal voluntary isometric torque and by plasma creatine kinase activity. Nine subjects had peak (day 4) creatine kinase activity exceeding 10,000 U/l. In this subgroup, CEBPB expression was elevated from baseline to 2 days post exercise (paired-samples t (1,8) = 3.72, p = 0.006). Related expression and selected cytokine changes after exercise did not reach significance. Muscle-damaging exercise in humans can be followed by induction of CEBPB transcript expression in peripheral blood. Associations between CEBPB expression in blood and muscle strength may be consistent with the CEBPB-dependent muscle repair process.
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Author URL.
Holly AC, Grellscheid S, van de Walle P, Dolan D, Pilling LC, Daniels DJ, von Zglinicki T, Ferrucci L, Melzer D, Harries LW, et al (2015). Comparison of senescence-associated miRNAs in primary skin and lung fibroblasts.
Biogerontology,
16(4), 423-434.
Abstract:
Comparison of senescence-associated miRNAs in primary skin and lung fibroblasts.
MicroRNAs are non-coding RNAs with roles in many cellular processes. Tissue-specific miRNA profiles associated with senescence have been described for several cell and tissue types. We aimed to characterise miRNAs involved in core, rather than tissue-specific, senescence pathways by assessment of common miRNA expression differences in two different cell types, with follow-up of predicted targets in human peripheral blood. MicroRNAs were profiled in early and late passage primary lung and skin fibroblasts to identify commonly-deregulated miRNAs. Expression changes of their bioinformatically-predicted mRNA targets were then assessed in both cell types and in human peripheral blood from elderly participants in the InCHIANTI study. 57/178 and 26/492 microRNAs were altered in late passage skin and lung cells respectively. Three miRNAs (miR-92a, miR-15b and miR-125a-3p) were altered in both tissues. 14 mRNA targets of the common miRNAs were expressed in lung and skin fibroblasts, of which two demonstrated up-regulation in late passage skin and lung cells (LYST; p = 0.02 [skin] and 0.02 [lung] INMT; p = 0.03 [skin] and 0.04 [lung]). ZMPSTE24 and LHFPL2 demonstrated altered expression in late passage skin cells only (p = 0.01 and 0.05 respectively). LHFPL2 was also positively correlated with age in peripheral blood (p value = 6.6 × 10(-5)). We find that the majority of senescence-associated miRNAs demonstrate tissue-specific effects. However, miRNAs showing common effects across tissue types may represent those associated with core, rather than tissue-specific senescence processes.
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Author URL.
Pfeiffer L, Wahl S, Pilling LC, Reischl E, Sandling JK, Kunze S, Holdt LM, Kretschmer A, Schramm K, Adamski J, et al (2015). DNA methylation of lipid-related genes affects blood lipid levels.
Circ Cardiovasc Genet,
8(2), 334-342.
Abstract:
DNA methylation of lipid-related genes affects blood lipid levels.
BACKGROUND: Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. METHODS AND RESULTS: Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (β coefficient=-0.049; P=8.26E-17) and triglyceride levels (β=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). CONCLUSIONS: Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.
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Author URL.
Pilling LC, Joehanes R, Melzer D, Harries LW, Henley W, Dupuis J, Lin H, Mitchell M, Hernandez D, Ying S-X, et al (2015). Gene expression markers of age-related inflammation in two human cohorts.
Exp Gerontol,
70, 37-45.
Abstract:
Gene expression markers of age-related inflammation in two human cohorts.
INTRODUCTION: Chronically elevated circulating inflammatory markers are common in older persons but mechanisms are unclear. Many blood transcripts (>800 genes) are associated with interleukin-6 protein levels (IL6) independent of age. We aimed to identify gene transcripts statistically mediating, as drivers or responders, the increasing levels of IL6 protein in blood at older ages. METHODS: Blood derived in-vivo RNA from the Framingham Heart Study (FHS, n=2422, ages 40-92 yrs) and InCHIANTI study (n=694, ages 30-104 yrs), with Affymetrix and Illumina expression arrays respectively (>17,000 genes tested), were tested for statistical mediation of the age-IL6 association using resampling techniques, adjusted for confounders and multiple testing. RESULTS: in FHS, IL6 expression was not associated with IL6 protein levels in blood. 102 genes (0.6% of 17,324 expressed) statistically mediated the age-IL6 association of which 25 replicated in InCHIANTI (including 5 of the 10 largest effect genes). The largest effect gene (SLC4A10, coding for NCBE, a sodium bicarbonate transporter) mediated 19% (adjusted CI 8.9 to 34.1%) and replicated by PCR in InCHIANTI (n=194, 35.6% mediated, p=0.01). Other replicated mediators included PRF1 (perforin, a cytolytic protein in cytotoxic T lymphocytes and NK cells) and IL1B (Interleukin 1 beta): few other cytokines were significant mediators. CONCLUSIONS: This transcriptome-wide study on human blood identified a small distinct set of genes that statistically mediate the age-IL6 association. Findings are robust across two cohorts and different expression technologies. Raised IL6 levels may not derive from circulating white cells in age related inflammation.
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Galloway TS, Fletcher T, Thomas OJ, Lee BP, Pilling LC, Harries LW (2015). PFOA and PFOS are associated with reduced expression of the parathyroid hormone 2 receptor (PTH2R) gene in women.
Chemosphere,
120, 555-562.
Abstract:
PFOA and PFOS are associated with reduced expression of the parathyroid hormone 2 receptor (PTH2R) gene in women.
Little is known about interactions between environmental and genetic risk factors for osteoarthritis (OA). Genetic factors include variation or mutation in genes involved in parathyroid hormone signalling. Exposure to the endocrine disrupting chemicals perfluoro-octanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) have been suggested as potential environmental contributors, although evidence to support this association is conflicting. Here we test the hypothesis that PFOA and PFOS may alter the mRNA expression of genes in the parathyroid signalling cascade to provide evidence on possible pathways between these chemicals and OA. We measured the relationship between PFOA or PFOS serum levels and the in vivo expression of the Parathyroid hormone 1 and 2 genes (PTH, PTH2), Parathyroid hormone 1 and 2 receptor genes (PTH1R, PTH2R) and the parathyroid hormone-like (PTHLH) gene in peripheral blood from a cross-sectional population study designed to assess the potential health effects of these chemicals. We used multivariate linear regression models and found that PFOA or PFOS was inversely correlated with parathyroid hormone 2 receptor (PTH2R) expression (coefficients=-0.43 and -0.32, p=p=0.017 and 0.006 for PFOA and PFOS respectively) in 189 female subjects. The levels of PTH2 transcripts encoding the ligand of PTH2r, were also found to be lower in women with OA (median 2.08) compared with controls (median 3.41, p=0.046). As the parathyroid signalling cascade is a known candidate for osteoarthritis risk and our findings raise the possibility that exposure to these chemicals may contribute to the pathogenesis of OA in some individuals.
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Peters MJ, Joehanes R, Pilling LC, Schurmann C, Conneely KN, Powell J, Reinmaa E, Sutphin GL, Zhernakova A, Schramm K, et al (2015). The transcriptional landscape of age in human peripheral blood.
Nat Commun,
6Abstract:
The transcriptional landscape of age in human peripheral blood.
Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
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2014
Winiarski BK, Cope N, Alexander M, Pilling LC, Warren S, Acheson N, Gutowski NJ, Whatmore JL (2014). Clinical Relevance of Increased Endothelial and Mesothelial Expression of Proangiogenic Proteases and VEGFA in the Omentum of Patients with Metastatic Ovarian High-Grade Serous Carcinoma.
Transl Oncol,
7(2), 267-276.e4.
Abstract:
Clinical Relevance of Increased Endothelial and Mesothelial Expression of Proangiogenic Proteases and VEGFA in the Omentum of Patients with Metastatic Ovarian High-Grade Serous Carcinoma.
Epithelial ovarian cancer (EOC) metastasis to the omentum requires implantation and angiogenesis. We propose that prometastatic changes in the omental endothelium (for angiogenesis) and mesothelium (for implantation) are critical. We investigated the expression of angiogenic proteases [cathepsin D (CD), cathepsin L (CL), and matrix metalloproteinase 2 (MMP2) and MMP9] and vascular endothelial growth factor a (VEGFA) in the mesothelium and endothelium of omentum from patients with EOC with omental metastases and control patients with benign ovarian tumors. Endothelial expression of CL, VEGFA, and MMP9 and mesothelial expression of VEGFA, MMP9, and CD were significantly increased in patients with metastasized EOC. High expression of MMP9 and VEGFA in endothelium and mesothelium and CD in mesothelium was positively associated with poor disease-specific survival (DSS). High MMP9 expression in either endothelium or mesothelium and presence of ascites prospectively showed the greatest risk of shorter DSS [hazard ratio (HR)= 6.16, 95% confidence interval (CI) = 1.76-21.6, P =. 0045; HR = 11.42, 95% CI = 2.59-50.35, P =. 0013; and HR = 6.35, 95% CI = 2.01-20.1, P =. 002, respectively]. High endothelial MMP9 expression and ascites were independent predictors of reduced DSS and overall survival, together resulting in worst patient prognosis. Our data show that omental metastasis of EOC is associated with increased proangiogenic protein expression in the omental endothelium and mesothelium.
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Holly AC, Pilling LC, Hernandez D, Lee BP, Singleton A, Ferrucci L, Melzer D, Harries LW (2014). Splicing factor 3B1 hypomethylation is associated with altered SF3B1 transcript expression in older humans.
Mech Ageing Dev,
135, 50-56.
Abstract:
Splicing factor 3B1 hypomethylation is associated with altered SF3B1 transcript expression in older humans.
Ageing in man is associated with changes to the splicing factor pool. A proportion of splicing factors are regulated during ageing by mechanisms involving the Ataxia Telangiectasia Mutated (ATM) gene, but the factors that determine the remaining proportion have yet to be identified. DNA methylation is known to be an important regulatory mechanism of gene expression. We assessed age-associated methylation and expression levels for 27 splicing factor genes, in peripheral blood samples from the InCHIANTI study. Examination of splicing patterns at specific loci was examined in a second cohort, the Exeter 10000 study. 27/502 methylation probes in 17 different genes were associated with age. Most changes were not associated with transcript expression levels or splicing patterns, but hypomethylation of the SF3B1 promoter region was found to mediate 53% of the relationship between age and transcript expression at this locus (p=0.02). DNA methylation does not appear to play a major role in regulation of the splicing factors, but changes in SF3B1 expression may be attributable to promoter hypomethylation at this locus. SF3B1 encodes a critical component of the U2 snRNP; altered expression of this gene may therefore contribute to the loss of regulated mRNA splicing that occurs with age.
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Lin H, Joehanes R, Pilling LC, Dupuis J, Lunetta KL, Ying S-X, Benjamin EJ, Hernandez D, Singleton A, Melzer D, et al (2014). Whole blood gene expression and interleukin-6 levels.
Genomics,
104(6 Pt B), 490-495.
Abstract:
Whole blood gene expression and interleukin-6 levels.
BACKGROUND: Circulating interleukin-6 levels increase with advancing age and are a risk factor for various diseases and mortality. The characterization of gene expression profiles associated with interleukin-6 levels might suggest important molecular events underlying its regulation. METHODS AND RESULTS: We studied the association of transcriptional profiles with interleukin-6 levels in 2422 participants from the Framingham Heart Study Offspring Cohort using Affymetrix Human Exon 1.0 ST Array. We identified 4139 genes that were significantly associated with interleukin-6 levels (FDR
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2013
Hek K, Demirkan A, Lahti J, Terracciano A, Teumer A, Cornelis MC, Amin N, Bakshis E, Baumert J, Ding J, et al (2013). A genome-wide association study of depressive symptoms.
Biol Psychiatry,
73(7), 667-678.
Abstract:
A genome-wide association study of depressive symptoms.
BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: in this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p
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Harries LW, Pilling LC, Lampron A, Rivest S, Melzer D (2013). Alzheimer’s pathology: should peripheral monocytes and CCR2 take center stage?. Neurodegenerative Disease Management, 3(1), 9-12.
Fletcher T, Galloway TS, Melzer D, Holcroft P, Cipelli R, Pilling LC, Mondal D, Luster M, Harries LW (2013). Associations between PFOA, PFOS and changes in the expression of genes involved in cholesterol metabolism in humans.
Environ Int,
57-58, 2-10.
Abstract:
Associations between PFOA, PFOS and changes in the expression of genes involved in cholesterol metabolism in humans.
Perfluorooctanoic acid (PFOA, 'C8') and perfluoroctane sulphonate (PFOS) are environmentally stable compounds with industrial and consumer uses and long half-lives in humans. Concern has been raised over chronic exposure effects to human health, especially in relation to cholesterol metabolism. Here, we explore the association between exposure to PFOA and PFOS and the in vivo expression of genes involved in cholesterol metabolism. We studied 290 individuals exposed to background levels of PFOS and elevated concentrations of PFOA through drinking water. Using adjusted linear regression models, we found inverse associations between serum PFOA levels and the whole blood expression level of genes involved in cholesterol transport (NR1H2, NPC1 and ABCG1; p=0.002, 0.026 and 0.014 respectively). A positive association was seen between PFOS and a transcript involved in cholesterol mobilisation (NCEH1; p=0.018), and a negative relationship with a transcript involved in cholesterol transport (NR1H3; p=0.044). When sexes were analysed separately, reductions in the levels of mRNAs involved in cholesterol transport were seen with PFOA in men (NPC1, ABCG1, and PPARA; p=0.025, 0.024 and 0.012 respectively) and in women (NR1H2 expression; p=0.019), whereas an increase in the levels of a cholesterol mobilisation transcript (NCEH1; p=0.036) was noted in women alone. PFOS was positively associated with expression of genes involved in both cholesterol mobilisation and transport in women (NCEH1 and PPARA; p=0.003 and 0.039 respectively), but no effects were evident in men. This is the first report of associations between the in vivo expression of genes involved in cholesterol metabolism and exposure to PFOA or PFOS, suggested that exposure to these compounds may promote a hypercholesterolaemic environment, with wider implications for human disease.
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Holly AC, Melzer D, Pilling LC, Fellows AC, Tanaka T, Ferrucci L, Harries LW (2013). Changes in splicing factor expression are associated with advancing age in man.
Mech Ageing Dev,
134(9), 356-366.
Abstract:
Changes in splicing factor expression are associated with advancing age in man.
Human ageing is associated with decreased cellular plasticity and adaptability. Changes in alternative splicing with advancing age have been reported in man, which may arise from age-related alterations in splicing factor expression. We determined whether the mRNA expression of key splicing factors differed with age, by microarray analysis in blood from two human populations and by qRT-PCR in senescent primary fibroblasts and endothelial cells. Potential regulators of splicing factor expression were investigated by siRNA analysis. Approximately one third of splicing factors demonstrated age-related transcript expression changes in two human populations. Ataxia Telangiectasia Mutated (ATM) transcript expression correlated with splicing factor expression in human microarray data. Senescent primary fibroblasts and endothelial cells also demonstrated alterations in splicing factor expression, and changes in alternative splicing. Targeted knockdown of the ATM gene in primary fibroblasts resulted in up-regulation of some age-responsive splicing factor transcripts. We conclude that isoform ratios and splicing factor expression alters with age in vivo and in vitro, and that ATM may have an inhibitory role on the expression of some splicing factors. These findings suggest for the first time that ATM, a core element in the DNA damage response, is a key regulator of the splicing machinery in man.
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Melzer D, Pilling LC, Fellows AD, Holly AC, Harries LW, Ferrucci L (2013). Gene Expression Biomarkers and Longevity. Annual Review of Gerontology and Geriatrics, 33(1), 233-258.
Holly AC, Melzer D, Pilling LC, Henley W, Hernandez DG, Singleton AB, Bandinelli S, Guralnik JM, Ferrucci L, Harries LW, et al (2013). Towards a gene expression biomarker set for human biological age.
Aging Cell,
12(2), 324-326.
Abstract:
Towards a gene expression biomarker set for human biological age
We have previously described a statistical model capable of distinguishing young (age
Abstract.
Dutta A, Henley W, Pilling LC, Wallace RB, Melzer D (2013). Uric acid measurement improves prediction of cardiovascular mortality in later life.
J Am Geriatr Soc,
61(3), 319-326.
Abstract:
Uric acid measurement improves prediction of cardiovascular mortality in later life.
OBJECTIVES: to estimate the association between uric acid and cardiovascular mortality in older adults, independent of traditional risk factors, and to estimate the risk prediction gain by adding uric acid measurements to the Framingham Cardiovascular Risk Score (FCRS). DESIGN: Longitudinal observational study of two population-based cohorts. SETTING: the Established Populations for Epidemiologic Studies of the Elderly, Iowa (Iowa-EPESE) and the Third National Health and Nutritional Examination Survey (NHANES III). PARTICIPANTS: One thousand twenty-eight Iowa-EPESE participants and 1,316 NHANES III participants. Selected participants were aged 70 and older without overt cardiovascular disease, renal dysfunction, or diuretic use who lived for 3 years or longer after baseline. MEASUREMENTS: Outcome was age at cardiovascular death during follow-up (12–20 years). Uric acid and cardiovascular risk factors such as smoking, systolic blood pressure, diabetes mellitus, obesity, serum cholesterol, and high-density lipoprotein cholesterol were measured at baseline. RESULTS: High serum uric acid (>7.0 mg/dL) was associated with male sex, obesity, lipid levels, and estimated glomerular filtration rate at baseline. Fully adjusted hazard ratios (HRs) for cardiovascular death with high uric acid versus normal were 1.36 (95% confidence interval (CI) = 1.10–1.69) in Iowa-EPESE and 1.43 (95% CI = 1.04–1.99) in NHANES III; pooled HR was 1.38 (95% CI = 1.16–1.61). The net reclassification improvement achieved by adding uric acid measurement to the FCRS was 9% to 20%. CONCLUSION: in individuals aged 70 and older without overt CVD, renal dysfunction, or diuretic use, serum uric acid greater than 7.0 mg/dL was associated with greater CVD mortality independent of classic CVD risk factors. Adding uric acid measurement to the FCRS would improve prediction in older adults.
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2012
Harries LW, Fellows AD, Pilling LC, Hernandez D, Singleton A, Bandinelli S, Guralnik J, Powell J, Ferrucci L, Melzer D, et al (2012). Advancing age is associated with gene expression changes resembling mTOR inhibition: evidence from two human populations.
Mech Ageing Dev,
133(8), 556-562.
Abstract:
Advancing age is associated with gene expression changes resembling mTOR inhibition: evidence from two human populations.
Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear. We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). Expression of 27/56 (InCHIANTI) and 19/44 (SAFHS) genes were associated with age after correction for multiple testing. 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets. We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people.
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Author URL.
Fellows AD, Holly AC, Pilling LC, Melzer D, Harries LW (2012). Age related changes in mTOR-related gene expression in two primary human cell lines. Healthy Aging Research
Harries LW, Pilling LC, Hernandez LDG, Bradley-Smith R, Henley W, Singleton AB, Guralnik JM, Bandinelli S, Ferrucci L, Melzer D, et al (2012). CCAAT-enhancer-binding protein-beta expression in vivo is associated with muscle strength.
Aging Cell,
11(2), 262-268.
Abstract:
CCAAT-enhancer-binding protein-beta expression in vivo is associated with muscle strength.
Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β)-triggered macrophage-mediated muscle fiber regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population. We undertook a genome-wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (aged 30 and 104). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery (SPPB) score tested walk speed, chair stand, and balance. CEBPB expression levels were associated with muscle strength (β coefficient = 0.20560, P = 1.03*10(-6), false discovery rate q = 0.014). The estimated handgrip strength in 70-year-old men in the lowest CEBPB expression tertile was 35.2 kg compared with 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle, and shoulder strength and the SPPB score (P = 0.018). Near-study-wide associations were also noted for TGF-β3 (P = 3.4*10(-5) , q = 0.12) and CEBPD expression (P = 9.7*10(-5) , q = 0.18) but not for CEBPA expression. We report here a novel finding that raised CEBPB expression in circulating leukocyte-derived RNA samples in vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB-triggered muscle repair: if this mechanism is confirmed, it may provide a target for intervention to protect and enhance aging muscle.
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Pilling LC, Harries LW, Powell J, Llewellyn DJ, Ferrucci L, Melzer D (2012). Genomics and successful aging: grounds for renewed optimism?.
J Gerontol a Biol Sci Med Sci,
67(5), 511-519.
Abstract:
Genomics and successful aging: grounds for renewed optimism?
BACKGROUND: Successful aging depends in part on delaying age-related disease onsets until later in life. Conditions including coronary artery disease, Alzheimer's disease, prostate cancer, and type 2 diabetes are moderately heritable. Genome-wide association studies have identified many risk associated single-nucleotide polymorphisms for these conditions, but much heritability remains unaccounted for. Nevertheless, a great deal is being learned. METHODS: Here, we review age-related disease associated single-nucleotide polymorphisms and identify key underlying pathways including lipid handling, specific immune processes, early tissue development, and cell cycle control. RESULTS: Most age-related disease associated single-nucleotide polymorphisms do not affect coding regions of genes or protein makeup but instead influence regulation of gene expression. Recent evidence indicates that evolution of gene regulatory sites is fundamental to interspecies differences. Animal models relevant to human aging may therefore need to focus more on gene regulation rather than testing major disruptions to fundamental pathway genes. Recent larger scale human studies of in vivo genome-wide expression (notably from the InCHIANTI aging study) have identified changes in splicing, the "fine tuning" of protein sequences, as a potentially important factor in decline of cellular function with age. Studies of expression with muscle strength and cognition have shown striking concordance with certain mice models of muscle repair and beta-amyloid phagocytosis respectively. CONCLUSIONS: the emerging clearer picture of the genetic architecture of age-related diseases in humans is providing new insights into the underlying pathophysiological pathways involved. Translation of genomics into new approaches to prevention, tests and treatments to extend successful aging is therefore likely in the coming decades.
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Harries LW, Bradley-Smith RM, Llewellyn DJ, Pilling LC, Fellows A, Henley W, Hernandez D, Guralnik JM, Bandinelli S, Singleton A, et al (2012). Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults.
Rejuvenation Res,
15(4), 395-404.
Abstract:
Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults.
INTRODUCTION: Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample. METHODS: We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models. RESULTS: in genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta=-0.16, p=5.1×10(-6), false discovery rate (FDR; q=0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta=-0.16, p=5.1×10(-6), q=0.003; and beta=-0.13, p=5.5×10(-5), q=0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype. CONCLUSIONS: We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated β-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.
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2011
Melzer D, Harries L, Pilling L, Bandinelli S, Guralnik JM, Singleton A, Hernandez D, Ferrucci L (2011). CONFIRMATION OF MOUSE MODEL OF SARCOPENIA BY GENOME WIDE EXPRESSION STUDY IN HUMANS.
GERONTOLOGIST,
51, 506-507.
Author URL.
