Dataset Information

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

ABSTRACT: Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

SUBMITTER: Cardona A

PROVIDER: S-EPMC6868468 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Cardona Alexia A Day Felix R FR Perry John R B JRB Loh Marie M Chu Audrey Y AY Lehne Benjamin B Paul Dirk S DS Lotta Luca A LA Stewart Isobel D ID Kerrison Nicola D ND Scott Robert A RA Khaw Kay-Tee KT Forouhi Nita G NG Langenberg Claudia C Liu Chunyu C Mendelson Michael M MM Levy Daniel D Beck Stephan S Leslie R David RD Dupuis Josée J Meigs James B JB Kooner Jaspal S JS Pihlajamäki Jussi J Vaag Allan A Perfilyev Alexander A Ling Charlotte C Hivert Marie-France MF Chambers John C JC Wareham Nicholas J NJ Ong Ken K KK

Diabetes 20190910 12

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onse ...[more]

PMID: 31506343

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Project description:To determine the association between systemic medication use and intraocular pressure (IOP) in a population of older British men and women.Population-based, cross-sectional study.We included 7093 participants from the European Prospective Investigation into Cancer-Norfolk Eye Study. Exclusion criteria were a history of glaucoma therapy (medical, laser, or surgical), IOP asymmetry between eyes of >5 mmHg, and missing data for any covariables. The mean age of participants was 68 years (range, 48-92) and 56% were women.We measured IOP using the Ocular Response Analyzer. Three readings were taken per eye and the best signal value of the Goldmann-correlated IOP value considered. Participants were asked to bring all their medications and related documentation to the health examination, and these were recorded by the research nurse using an electronic case record form. The medication classes examined were angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, ?-blockers, ?-blockers, calcium channel blockers, diuretics, nitrates, statins, insulin, biguanides, sulfonylureas, aspirin, and other nonsteroidal anti-inflammatory drugs. We examined associations between medication use and IOP using multivariable linear regression models adjusted for age, sex, and body mass index. Models containing diabetic medication were further adjusted for glycosylated hemoglobin levels.Mean IOP of the right and left eyes.Use of systemic ?-blockers (-0.92 mmHg; 95% CI, -1.19, -0.65; P<0.001) and nitrates (-0.63 mmHg; 95% CI, -1.12, -0.14; P = 0.011) were independently associated with lower IOP. The observed associations between statin or aspirin use with IOP were no longer significant after adjustment for ?-blocker use.This is the first population-based study to demonstrate and quantify clinically significant differences in IOP among participants using systemic ?-blockers or nitrates. Lower IOP observed in participants using statins or aspirin was explained by concurrent systemic ?-blocker use. The study findings may have implications for the management of glaucoma patients with comorbidity, and may provide insight into the pathophysiologic processes underlying IOP.

Project description:Background and Purpose- Fatigue is a common symptom among stroke survivors and in general practice. However, the clinical significance of fatigue and its relationship to incident stroke is unclear. The aim of this study was to examine the relationship between self-reported fatigue and the incidence of stroke in a general population. Methods- This was a prospective, population-based study. The study population was 15 654 men and women aged 39 to 79 years recruited in 1993 to 1997 and followed till March 2016. Fatigue was assessed at 18 months after baseline using the vitality domain of the Short Form 36 questionnaire. Cox proportional hazard models were constructed to describe the prospective relationship between baseline fatigue and incident stroke adjusting for age, sex, systolic blood pressure, cholesterol, physical activity, smoking status, alcohol consumption, fruit and vegetable consumption, diabetes mellitus, body mass index, vitamin supplement use, education level, Townsend deprivation index, and occupational social class. Incident stroke was ascertained using death certificates and hospital record linkage data. Results- Through 249 248 person-years of follow-up, 1509 incident strokes occurred. Participants who reported the highest level of fatigue (quartile 4) were more likely to be women, to be multimorbid, and to perceive their health as fair or poor. We observed ≈50% relative risk increase in stroke risk (hazard ratio, 1.49 [95% CI, 1.29-1.71]) in those who reported the highest level of fatigue compared with those who reported the lowest level of fatigue (Q4 versus Q1). This relationship remained unaltered regardless of anemia status, the presence or absence of chronic bronchitis, thyroid dysfunction, or depression. Conclusions- Self-report fatigue assessed by the vitality domain of the Short Form 36 questionnaire predicts the risk of future stroke at the general population level. Identifying and addressing stroke risk factors in those who report fatigue in general practice may have substantial benefit at the population level.

Project description:OBJECTIVE:Apolipoprotein C-III (apoC-III) is a key regulator of triglyceride metabolism. Elevated triglyceride-rich lipoproteins and apoC-III levels are causally linked to coronary artery disease (CAD) risk. The mechanism(s) through which apoC-III increases CAD risk remains largely unknown. The aim was to confirm the association between apoC-III plasma levels and CAD risk and to explore which lipoprotein subfractions contribute to this relationship between apoC-III and CAD risk. APPROACH AND RESULTS:Plasma apoC-III levels were measured in baseline samples from a nested case-control study in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. The study comprised 2711 apparently healthy study participants, of whom 832 subsequently developed CAD. We studied the association of baseline apoC-III levels with incident CAD risk, lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy and inflammatory biomarkers. ApoC-III levels were significantly associated with CAD risk (odds ratio, 1.91; 95% confidence interval, 1.48-2.48 for highest compared with lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio, 1.47; 95% confidence interval, 1.11-1.94). ApoC-III levels were positively correlated with triglyceride levels, (r=0.39), particle numbers of very-low-density lipoprotein (r=0.25), intermediate-density lipoprotein (r=0.23), small dense low-density lipoprotein (r=0.26), and high-sensitivity C-reactive protein (r=0.15), whereas an inverse correlation was observed with large low-density lipoprotein particle number (r=-0.11), P<0.001 for each. Mediation analysis indicated that the association between apoC-III and CAD risk could be explained by triglyceride elevation (triglyceride, very-low-density lipoprotein, and intermediate-density lipoprotein particles), small low-density lipoprotein particle size, and high-sensitivity C-reactive protein. CONCLUSIONS:ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense low-density lipoprotein, and low-grade inflammation may explain this association.

Project description:BackgroundCognition covers a range of abilities, such as memory, response time and language, with tests assessing either specific or generic aspects. However differences between measures may be observed within the same individuals.ObjectiveTo investigate the cross-sectional association of cognitive performance and socio-demographic factors using different assessment tools across a range of abilities in a British cohort study.MethodsParticipants of the European Prospective Investigation of Cancer (EPIC) in Norfolk Study, aged 48-92 years, underwent a cognitive assessment between 2006 and 2011 (piloted between 2004 and 2006) and were investigated over a different domains using a range of cognitive tests.ResultsCognitive measures were available on 8584 men and women. Though age, sex, education and social class were all independently associated with cognitive performance in multivariable analysis, different associations were observed for different cognitive tests. Increasing age was associated with increased risk of a poor performance score in all of the tests, except for the National Adult Reading Test (NART), an assessment of crystallized intelligence. Compared to women, men were more likely to have had poor performance for verbal episodic memory, Odds Ratio, OR = 1.99 (95% Confidence Interval, 95% CI 1.72, 2.31), attention OR = 1.62, (95% CI 1.39, 1.88) and prospective memory OR = 1.46, (95% CI 1.29, 1.64); however, no sex difference was observed for global cognition, OR = 1.07 (95%CI 0.93, 1.24). The association with education was strongest for NART, and weakest for processing speed.ConclusionAge, sex, education and social class were all independently associated with performance on cognitive tests assessing a range of different domains. However, the magnitude of associations of these factors with different cognitive tests differed. The varying relationships seen across different tests may help explain discrepancies in results reported in the current literature, and provides insights into influences on cognitive performance in later life.

Project description:BackgroundHeavy drinkers of alcohol are reported to use hospitals more than non-drinkers, but it is unclear whether light-to-moderate drinkers use hospitals more than non-drinkers.ObjectiveWe examined the relationship between alcohol consumption in 10,883 men and 12,857 women aged 40-79 years in the general population and subsequent admissions to hospital and time spent in hospital.MethodsParticipants from the EPIC-Norfolk prospective population-based study were followed for ten years (1999-2009) using record linkage.ResultsCompared to current non-drinkers, men who reported any alcohol drinking had a lower risk of spending more than twenty days in hospital multivariable adjusted OR 0.80 (95%CI 0.68-0.94) after adjusting for age, smoking status, education, social class, body mass index and prevalent diseases. Women who were current drinkers were less likely to have any hospital admissions multivariable adjusted OR 0.84 (95%CI 0.74-0.95), seven or more admissions OR 0.77 (95% CI 0.66-0.88) or more than twenty hospital days OR 0.70 (95%CI 0.62-0.80). However, compared to lifelong abstainers, men who were former drinkers had higher risk of any hospital admissions multivariable adjusted OR 2.22 (95%CI 1.51-3.28) and women former drinkers had higher risk of seven or more admissions OR 1.30 (95%CI 1.01-1.67).ConclusionCurrent alcohol consumption was associated with lower risk of future hospital usage compared with non-drinkers in this middle aged and older population. In men, this association may in part be due to whether former drinkers are included in the non-drinker reference group but in women, the association was consistent irrespective of the choice of reference group. In addition, there were few participants in this cohort with very high current alcohol intake. The measurement of past drinking, the separation of non-drinkers into former drinkers and lifelong abstainers and the choice of reference group are all influential in interpreting the risk of alcohol consumption on future hospitalisation.

Project description:DNA methylation studies of incident type 2 diabetes in US populations are limited, and to our knowledge none included individuals of African descent living in the US. We performed an epigenome-wide association analysis of blood-based methylation levels at CpG sites with incident type 2 diabetes using Cox regression in 2,091 Black and 1,029 White individuals from the Atherosclerosis Risk in Communities study. At an epigenome-wide significance threshold of 10-7, we detected 7 novel diabetes-associated CpG sites in C1orf151 (cg05380846: HR= 0.89, p = 8.4 × 10-12), ZNF2 (cg01585592: HR= 0.88, p = 1.6 × 10-9), JPH3 (cg16696007: HR= 0.87, p = 7.8 × 10-9), GPX6 (cg02793507: HR= 0.85, p = 2.7 × 10-8 and cg00647063: HR= 1.20, p = 2.5 × 10-8), chr17q25 (cg16865890: HR= 0.8, p = 6.9 × 10-8), and chr11p15 (cg13738793: HR= 1.11, p = 7.7 × 10-8). The CpG sites at C1orf151, ZNF2, JPH3 and GPX6, were identified in Black adults, chr17q25 was identified in White adults, and chr11p15 was identified upon meta-analyzing the two groups. The CpG sites at JPH3 and GPX6 were likely associated with incident type 2 diabetes independent of BMI. All the CpG sites, except at JPH3, were likely consequences of elevated glucose at baseline. We additionally replicated known type 2 diabetes-associated CpG sites including cg19693031 at TXNIP, cg00574958 at CPT1A, cg16567056 at PLBC2, cg11024682 at SREBF1, cg08857797 at VPS25, and cg06500161 at ABCG1, 3 of which were replicated in Black adults at the epigenome-wide threshold. We observed modest increase in type 2 diabetes variance explained upon addition of the significantly associated CpG sites to a Cox model that included traditional type 2 diabetes risk factors and fasting glucose (increase from 26.2% to 30.5% in Black adults; increase from 36.9% to 39.4% in White adults). We examined if groups of proximal CpG sites were associated with incident type 2 diabetes using a gene-region specific and a gene-region agnostic differentially methylated region (DMR) analysis. Our DMR analyses revealed several clusters of significant CpG sites, including a DMR consisting of a previously discovered CpG site at ADCY7 and promoter regions of TP63 which were differentially methylated across all race groups. This study illustrates improved discovery of CpG sites/regions by leveraging both individual CpG site and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g., GPX6, JPH3, and TP63), and future gene-specific methylation studies could elucidate the link between genes, environment, and methylation in the pathogenesis of type 2 diabetes.

Dataset Information

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Publications

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

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