BackgroundChronic 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.ResultsWe 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 < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.ConclusionWe have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10−7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a6causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

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.

No abstract

Findings show that DNA methylation patterns in adipose tissue are associated with adiposity.

Cumulative exposure to socioeconomic disadvantage across the life course may be inversely associated with coronary heart disease (CHD); the mechanisms are not fully clear. An objective of this study was to determine whether cumulative life-course socioeconomic position (SEP) is associated with CHD incidence in a well-characterized US cohort that had directly assessed childhood and adulthood measures of SEP and prospectively measured CHD incidence. Furthermore, analyses aimed to evaluate whether adjustment for CHD risk factors reduces the association between cumulative life-course SEP and CHD. The authors examined 1,835 subjects who participated in the Framingham Heart Study Offspring Cohort from 1971 through 2003 (mean age, 35.0 years; 52.4% women). Childhood SEP was measured as father's education; adulthood SEP was assessed as own education and occupation. CHD incidence included myocardial infarction, coronary insufficiency, and coronary death. Cox proportional hazards analyses indicated that cumulative SEP was associated with incident CHD after adjustment for age and sex (hazard ratio = 1.82, 95% confidence interval: 1.17, 2.85 for low vs. high cumulative SEP score). Adjustment for CHD risk factors reduced that magnitude of association (hazard ratio = 1.29, 95% confidence interval: 0.78, 2.13). These findings underscore the potential importance of CHD prevention and treatment efforts for those whose backgrounds include low SEP throughout life.

Epidemiological studies have demonstrated that genetic, environmental, behavioral, and clinical factors contribute to cardiovascular disease (CVD) development. How these risk factors interact at the cellular level to cause CVD is not well known. Epigenetic epidemiology enables researchers to explore critical links between genomic coding, modifiable exposures, and manifestation of disease phenotype. One epigenetic link, DNA methylation, is potentially an important mechanism underlying these associations. In the past decade, there has been a significant increase in the number of epidemiological studies investigating cardiovascular risk factors and outcomes in relation to DNA methylation, but many gaps remain in our understanding of the underlying etiology and biological implications. In this review we provide a brief overview of the biology and mechanisms of DNA methylation and its role in CVD. In addition, we summarize the current evidence base in epigenetic epidemiology studies relevant to cardiovascular health and disease, and discuss the limitations, challenges, and future directions of the field. Finally, we provide guidelines for well-designed epigenetic epidemiology studies, with particular focus on methodological aspects, study design, and analytical challenges.