期刊
CIRCULATION-CARDIOVASCULAR GENETICS
卷 10, 期 1, 页码 -出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.116.001487
关键词
cardiovascular diseases; DNA Methylation; epigenomics; gene expression; lipids
资金
- National Institutes of Health (NIH) [N01-HC-25195, HHSN2682015000011, P30 DK46200, 1R01DK106236-01A1, 1R01HL135313-01]
- Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), NIH
- NIH Director's Challenge Award
- Center for Information Technology, NIH, Bethesda, MD
- Tommy Kaplan Fund, Boston Children's Hospital
- Knut and Alice Wallenberg (KAW) Foundation
- Swedish Research Council (VR) [2012-1397]
- Swedish Heart-Lung Foundation [20120197]
- Uppsala University Hospital (ALF-medel)
- VR
- KAW Foundation
- UK Biotechnology and Biological Sciences Research Council (BBSRC)
- Royal Society
- Chief Scientist Office of the Scottish Government
- Age UK (The Disconnected Mind project)
- Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE)
- Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award)
- Wellcome Trust Institutional Strategic Support Fund
- University of Edinburgh
- University of Queensland
- BBSRC
- Medical Research Council
- University of Edinburgh , cross-council Lifelong Health and Wellbeing initiative [MR/K026992/1]
- National Health and Medical Research Council (NHMRC) [1010374]
- NIH National Heart, Lung and Blood Institute [R01 HL104135-01]
- European Community's Seventh Framework Programme (FP7)
- European Union
- National Institute for Health Research-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- Division of Intramural Research, NHLBI
- NHMRC Fellowship [1083656]
- National Health and Medical Research Council of Australia [1083656] Funding Source: NHMRC
- BBSRC [BB/F019394/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- British Heart Foundation [RG/14/5/30893] Funding Source: researchfish
- Chief Scientist Office [ETM/55, CZB/4/505] Funding Source: researchfish
- Medical Research Council [MR/K026992/1] Funding Source: researchfish
Background- Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. Methods and Results- To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P < 1.08E-07) and replicated 33 (at Bonferroni-corrected P < 0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglyceridesand high-density lipoprotein cholesterol (HDL- C; cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P= 7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P= 0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (P-TC = 0.004, PHDL-C = 0.008 and P-triglycerides = 0.00003) and coronary heart disease ( P= 0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. Conclusions-We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.
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