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

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

doi:10.1161/CIRCGENETICS.116.001487

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

Circ Cardiovasc Genet. 2017 Jan;10(1):e001487. doi: 10.1161/CIRCGENETICS.116.001487.

Authors

Åsa K Hedman¹, Michael M Mendelson¹, Riccardo E Marioni¹, Stefan Gustafsson¹, Roby Joehanes¹, Marguerite R Irvin¹, Degui Zhi¹, Johanna K Sandling¹, Chen Yao¹, Chunyu Liu¹, Liming Liang¹, Tianxiao Huan¹, Allan F McRae¹, Serkalem Demissie¹, Sonia Shah¹, John M Starr¹, L Adrienne Cupples¹, Panos Deloukas¹, Timothy D Spector¹, Johan Sundström¹, Ronald M Krauss¹, Donna K Arnett¹, Ian J Deary¹, Lars Lind¹, Daniel Levy¹, Erik Ingelsson²

Affiliations

¹ From the Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory (Å.K.H., S.G., E.I.) and Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory (J.K.S.), Uppsala University, Sweden; Cardiovascular Medicine unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden (Å.K.H.) Framingham Heart Study, MA (M.M.M., R.J., C.Y., C.L., T.H., S.D., L.A.C., D.L.); Department of Biostatistics (C.L., L.A.C., S.D.), Boston University, MA; Boston University, MA (M.M.M.); Department of Cardiology, Boston Children's Hospital, MA (M.M.M.); Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (M.M.M., R.J., C.Y., C.L., T.H., D.L.); Centre for Cognitive Ageing and Cognitive Epidemiology (R.E.M., J.M.S., I.J.D.), Medical Genetics Section, Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine (R.E.M.), Alzheimer Scotland Dementia Research Centre (J.M.S.), and Department of Psychology (I.J.D.), University of Edinburgh, United Kingdom; Queensland Brain Institute, The University of Queensland, Brisbane, Australia (R.E.M., A.F.M., S.S.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.S., A.F.M.); Hebrew Senior Life, Harvard Medical School, Boston, MA (R.J.); Department of Epidemiology, School of Public Health (M.R.I.) and Department of Biostatistics, Section on Statistical Genetics (D.Z.), University of Alabama at Birmingham; Department of Biostatistics, Harvard School of Public Health, Boston, MA (L. Liang); William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (P.D.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia (P.D.); Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom (T.D.S.); Deparment of Medical Sciences, Cardiovascular Epidemiology, Uppsala University Hospital, Sweden (J.S., L.L.); Children's Hospital Oakland Research Institute, CA (R.M.K.); College of Public Health, University of Kentucky, Lexington (D.K.A.); and Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (E.I.).
² From the Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory (Å.K.H., S.G., E.I.) and Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory (J.K.S.), Uppsala University, Sweden; Cardiovascular Medicine unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden (Å.K.H.) Framingham Heart Study, MA (M.M.M., R.J., C.Y., C.L., T.H., S.D., L.A.C., D.L.); Department of Biostatistics (C.L., L.A.C., S.D.), Boston University, MA; Boston University, MA (M.M.M.); Department of Cardiology, Boston Children's Hospital, MA (M.M.M.); Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (M.M.M., R.J., C.Y., C.L., T.H., D.L.); Centre for Cognitive Ageing and Cognitive Epidemiology (R.E.M., J.M.S., I.J.D.), Medical Genetics Section, Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine (R.E.M.), Alzheimer Scotland Dementia Research Centre (J.M.S.), and Department of Psychology (I.J.D.), University of Edinburgh, United Kingdom; Queensland Brain Institute, The University of Queensland, Brisbane, Australia (R.E.M., A.F.M., S.S.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.S., A.F.M.); Hebrew Senior Life, Harvard Medical School, Boston, MA (R.J.); Department of Epidemiology, School of Public Health (M.R.I.) and Department of Biostatistics, Section on Statistical Genetics (D.Z.), University of Alabama at Birmingham; Department of Biostatistics, Harvard School of Public Health, Boston, MA (L. Liang); William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (P.D.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia (P.D.); Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom (T.D.S.); Deparment of Medical Sciences, Cardiovascular Epidemiology, Uppsala University Hospital, Sweden (J.S., L.L.); Children's Hospital Oakland Research Institute, CA (R.M.K.); College of Public Health, University of Kentucky, Lexington (D.K.A.); and Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (E.I.). eriking@stanford.edu.

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 (P_TC=0.004, P_HDL-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.

Keywords: DNA Methylation; cardiovascular diseases; epigenomics; gene expression; lipids.

MeSH terms

Aged
Biomarkers / blood
Coronary Disease / blood
Coronary Disease / diagnosis
Coronary Disease / epidemiology
Coronary Disease / genetics*
CpG Islands
Cross-Sectional Studies
DNA Methylation*
Dyslipidemias / blood
Dyslipidemias / diagnosis
Dyslipidemias / epidemiology
Dyslipidemias / 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

Substances

Biomarkers
Lipids

Abstract

MeSH terms

Substances

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