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1.
Circulation ; 140(8): 645-657, 2019 08 20.
Article in English | MEDLINE | ID: mdl-31424985

ABSTRACT

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<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.


Subject(s)
Coronary Disease/diagnosis , CpG Islands/genetics , DNA Methylation/physiology , Leukocytes/physiology , Myocardial Infarction/diagnosis , Adult , Aged , Cohort Studies , Coronary Disease/epidemiology , Europe/epidemiology , Female , Genome-Wide Association Study , Humans , Incidence , Male , Middle Aged , Myocardial Infarction/epidemiology , Population Groups , Prognosis , Prospective Studies , Risk , United States/epidemiology
2.
PLoS Med ; 14(1): e1002215, 2017 Jan.
Article in English | MEDLINE | ID: mdl-28095459

ABSTRACT

BACKGROUND: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS AND FINDINGS: We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. CONCLUSIONS: We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.


Subject(s)
Body Mass Index , Coronary Artery Disease/genetics , DNA Methylation , Gene Expression Regulation , Leukocytes/metabolism , Lipid Metabolism , Aged , Coronary Artery Disease/etiology , Epigenesis, Genetic , Female , Genome-Wide Association Study/methods , Humans , Lipid Metabolism/genetics , Male , Mendelian Randomization Analysis , Obesity/complications , Oligonucleotide Array Sequence Analysis
3.
Cell Metab ; 21(1): 138-49, 2015 Jan 06.
Article in English | MEDLINE | ID: mdl-25565211

ABSTRACT

Using a functional approach to investigate the epigenetics of type 2 diabetes (T2D), we combine three lines of evidence-diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence-to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change are conserved. These regions overlap with 27 genetic T2D risk loci, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed four genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk.


Subject(s)
Diabetes Mellitus, Type 2/genetics , Epigenesis, Genetic , Adipocytes/cytology , Adipocytes/metabolism , Animals , Cells, Cultured , DNA Methylation , Diabetes Mellitus, Type 2/pathology , Diet, High-Fat , Gene Expression Regulation , Genetic Loci , Genome-Wide Association Study , Glucose Tolerance Test , Humans , Male , Mice , Mice, Inbred C57BL , Polymorphism, Single Nucleotide , RNA, Small Interfering/metabolism , Transcription Factor 7-Like 2 Protein/genetics
4.
Genome Biol ; 16: 25, 2015 Jan 30.
Article in English | MEDLINE | ID: mdl-25633388

ABSTRACT

BACKGROUND: DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age. RESULTS: Here we test whether differences between people's chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43. CONCLUSIONS: DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.


Subject(s)
Blood/metabolism , Cause of Death , DNA Methylation/genetics , Mortality , Aged , Aging/genetics , Cohort Studies , Demography , Female , Humans , Inheritance Patterns/genetics , Leukocyte Count , Male , Risk Factors , Survival Analysis
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