Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies.
Hedman, Asa K. PhD; Mendelson, Michael M. MD; Marioni, Riccardo E. PhD; Gustafsson, Stefan PhD; Joehanes, Roby PhD; Irvin, Marguerite R. PhD; Zhi, Degui PhD; Sandling, Johanna K. PhD; Yao, Chen PhD; Liu, Chunyu PhD; Liang, Liming PhD; Huan, Tianxiao PhD; McRae, Allan F. PhD; Demissie, Serkalem PhD; Shah, Sonia PhD; Starr, John M. MD, PhD; Cupples, L. Adrienne PhD; Deloukas, Panos PhD; Spector, Timothy D. MD; Sundstrom, Johan MD, PhD; Krauss, Ronald M. MD; Arnett, Donna K. PhD; Deary, Ian J. PhD; Lind, Lars MD, PhD; Levy, Daniel MD; Ingelsson, Erik MD, PhD
Circulation: Cardiovascular Genetics.
10(1):e001487, February 2017.
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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 triglycerides and 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 (PTC=0.004, PHDL-C=0.008 and Ptriglycerides=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.
(C) 2017 American Heart Association, Inc.