Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies.

Abstract

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.

• Authors: Åsa K Hedman, Michael M Mendelson, Riccardo E Marioni, Stefan Gustafsson, Roby Joehanes, Marguerite R Irvin, Degui Zhi, Johanna K Sandling, Chen Yao, Chunyu Liu, Liming Liang, Tianxiao Huan, Allan F McRae, Serkalem Demissie, Sonia Shah, John M Starr, L Adrienne Cupples, Panos Deloukas, Timothy D Spector, Johan Sundström, Ronald M Krauss, Donna K Arnett, Ian J Deary, Lars Lind, Daniel Levy, Erik Ingelsson
• Journal: Circulation. Cardiovascular genetics (Circ Cardiovasc Genet) Vol. 10 Issue 1 (Jan 2017) ISSN: 1942-3268 [Electronic] United States
• PMID: 28213390 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors.

Chemical References

• Biomarkers
• Lipids

Topics

• Aged
• Biomarkers (blood)
• Coronary Disease (blood, diagnosis, epidemiology, genetics)
• CpG Islands
• Cross-Sectional Studies
• DNA Methylation
• Dyslipidemias (blood, diagnosis, epidemiology, genetics)
• Epigenesis, Genetic
• Epigenomics (methods)
• Europe (epidemiology)
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Incidence
• Lipid Metabolism (genetics)
• Lipids (blood)
• Male
• Metabolomics (methods)
• Middle Aged
• Phenotype
• Prognosis
• Prospective Studies
• Quantitative Trait Loci
• Risk Assessment
• Risk Factors
• United States (epidemiology)