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Gomez Alonso, M.D.C. ; Kretschmer, A. ; Wilson, R. ; Pfeiffer, L. ; Karhunen, V.* ; Seppälä, I.* ; Zhang, W.* ; Mittelstraß, K. ; Wahl, S. ; Matias-Garcia, P.R. ; Prokisch, H. ; Horn, S. ; Meitinger, T. ; Serrano Garcia, L.R. ; Sebert, S.* ; Raitakari, O.* ; Loh, M.* ; Rathmann, W.* ; Müller-Nurasyid, M. ; Herder, C.* ; Roden, M.* ; Hurme, M.* ; Jarvelin, M.R.* ; Ala-Korpela, M.* ; Kooner, J.S.* ; Peters, A. ; Lehtimäki, T.* ; Gieger, C. ; Kettunen, J.* ; Waldenberger, M.

DNA methylation and lipid metabolism: An EWAS of 226 metabolic measures.

Clin. Epigenet. 13:7 (2021)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cpg Site ; Fatty Acids ; Hdl ; Ldl ; Lipoprotein Composition ; Lipoprotein Sizes ; Myocardial Infarction ; Nmr ; Obesity ; Vldl
ISSN (print) / ISBN 1868-7075
e-ISSN 1868-7083
Journal Clinical Epigenetics
Quellenangaben Volume: 13, Issue: 1, Pages: , Article Number: 7 Supplement: ,
Publisher Springer
Publishing Place Berlin : Heidelberg
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
Grants National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust
Joint Programming Initiative A healthy diet for a healthy life ()
Academy of Finland (FI)
EU Horizon 2020
Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals
Singapore Ministry of Health's National Medical Research Council
Department of Health
Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD)
Ministry of Science and Culture of the State North Rhine-Westphalia
German Federal Ministry of Health
German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative "A Healthy Diet for a Healthy Life"
German Research Foundation
Ludwig-Maximilians-Universitat, as part of LMUinnovativ
Munich Center of Health Sciences (MC-Health)
State of Bavaria
Deutsche Forschungsgemeinschaft (DE)
National Institute for Health Research
British Heart Foundation
Medical Research Council
European Union FP7
H2020 programs

Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award
Finnish Cultural Foundation
Finnish Foundation for Cardiovascular research
Paavo Nurmi Foundation
Juho Vainio Foundation
Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere, and Turku University Hospitals
Social Insurance Institution of Finland
Sigrid Juselius Foundation
Tampere Tuberculosis Foundation
Emil Aaltonen Foundation
Sigrid Juselius Foundation, Finland
Consejo Nacional de Ciencia y Tecnologia (CONACyT)Mexico
JPI-HDHL program
Tampere University Hospital Supporting Foundation
European Research Council
Signe and Ane Gyllenberg Foundation
Diabetes Research Foundation of Finnish Diabetes Association
Yrjo Jahnsson Foundation
NIHR Official Development Assistance (ODA)
NIHR
Academy of Finland
European Union
Wellcome Trust