TY - JOUR
T1 - Epigenetic Patterns in Blood Associated with Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results from Genome-Wide Association Studies
AU - Hedman, Åsa K.
AU - Mendelson, Michael M.
AU - Marioni, Riccardo E.
AU - Gustafsson, Stefan
AU - Joehanes, Roby
AU - Irvin, Marguerite R.
AU - Zhi, Degui
AU - Sandling, Johanna K.
AU - Yao, Chen
AU - Liu, Chunyu
AU - Liang, Liming
AU - Huan, Tianxiao
AU - McRae, Allan F.
AU - Demissie, Serkalem
AU - Shah, Sonia
AU - Starr, John M.
AU - Cupples, L. Adrienne
AU - Deloukas, Panos
AU - Spector, Timothy D.
AU - Sundström, Johan
AU - Krauss, Ronald M.
AU - Arnett, Donna K.
AU - Deary, Ian J.
AU - Lind, Lars
AU - Levy, Daniel
AU - Ingelsson, Erik
N1 - Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
KW - DNA Methylation
KW - cardiovascular diseases
KW - epigenomics
KW - gene expression
KW - lipids
UR - http://www.scopus.com/inward/record.url?scp=85013491477&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013491477&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.116.001487
DO - 10.1161/CIRCGENETICS.116.001487
M3 - Article
C2 - 28213390
AN - SCOPUS:85013491477
SN - 1942-325X
VL - 10
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 1
M1 - 001487
ER -
