University of Oulu

Gomez-Alonso, M.C., Kretschmer, A., Wilson, R. et al. DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures. Clin Epigenet 13, 7 (2021).

DNA methylation and lipid metabolism : an EWAS of 226 metabolic measures

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Author: Gomez-Alonso, Monica del C.1,2; Kretschmer, Anja1,2; Wilson, Rory1,2;
Organizations: 1German Res Ctr Environm Hlth, Inst Epidemiol, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Ingolstaedter Landstr 1, D-85764 Neuherberg, Germany.
2German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.
3Imperial Coll London, Dept Epidemiol & Biostat, London, England.
4Univ Oulu, Oulu Univ Hosp, Ctr Life Course Hlth Res, Oulu, Finland.
5Tampere Univ, Pirkanmaa Hosp Dist, Dept Clin Chem, Fimlab Labs, Tampere, Finland.
6Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr, Tampere, Finland.
7London North West Univ Healthcare NHS Trust, Ealing Hosp, Dept Cardiol, London, Middx, England.
8German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany.
9Tech Univ Munich, Sch Med, Inst Human Genet, Munich, Germany.
10German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
11Tech Univ Munich, Chair Microbiol, Freising Weihenstephan, Germany.
12Univ Turku, Turku Univ Hosp, Ctr Populat Hlth Res, Turku, Finland.
13Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
14Univ Turku, Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.
15Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore.
16Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Biometr & Epidemiol, Dusseldorf, Germany.
17German Ctr Diabet Res DZD, Munich, Germany.
18Ludwig Maximilians Univ Munchen, Fac Med, IBE, Chair Genet Epidemiol, Munich, Germany.
19German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.
20Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Med Biostat Epidemiol & Informat IMBEI, D-55101 Mainz, Germany.
21Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany.
22Heinrich Heine Univ Dusseldorf, Med Fac, Div Endocrinol & Diabetol, Dusseldorf, Germany.
23TampereUniversity, Fac Med & Hlth Technol, Dept Microbiol & Immunol, Tampere, Finland.
24Imperial Coll London, UKMRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London, England.
25Brunel Univ London, Coll Hlth & Life Sci, Dept Life Sci, London, England.
26Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland.
27Univ Oulu, Fac Med, Computat Med, Oulu, Finland.
28Univ Oulu, Bioctr Oulu, Oulu, Finland.
29Imperial Coll London, Natl Heart & Lung Inst, London, England.
30Imperial Coll Healthcare NHS Trust, London, England.
31Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
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Language: English
Published: Springer Nature, 2021
Publish Date: 2021-04-28


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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Series: Clinical epigenetics
ISSN: 1868-7075
ISSN-E: 1868-7083
ISSN-L: 1868-7075
Volume: 13
Issue: 1
Article number: 7
DOI: 10.1186/s13148-020-00957-8
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. This work was supported by a Grant (WA 4081/1-1) from the German Research Foundation and by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative “A Healthy Diet for a Healthy Life” (01EA1902A: Dimension). The German Diabetes Center (DDZ) is funded by the German Federal Ministry of Health and the Ministry of Science and Culture of the State North Rhine-Westphalia. This study was supported in part by a Grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381), the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143), and H2020 programs (iHealth-T2D, 643774). The Young Finns Study has been financially supported by the Academy of Finland: Grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere, and Turku University Hospitals (Grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (Grant 755320 for TAXINOMISIS; Grant 848146 for To_Aition); European Research Council (Grant 742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation. The NFBC1966 team acknowledges funding from the following: European Union’s Horizon 2020 research and innovation programme [DYNAHEALTH 633595, LIFECYCLE 733206, EUCANCONNECT 824989, LongITools 874739, EarlyCause 848458], Academy of Finland [EGEA 285547], and the JPI-HDHL program [PREcise – MRC-UK P75416]. MCGA holds a scholarship from the Consejo Nacional de Ciencia y Tecnología (CONACyT)-México. MAK was supported by a research Grant from the Sigrid Juselius Foundation, Finland. JC is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). The funders had no role in study design or data collection, analysis, and interpretation. The funding sources had no influence in the study design, collection, analysis, interpretation of data, writing of the report, and in the decision to submit the article.
EU Grant Number: (643774) iHealth-T2D - Family-based intervention to improve healthy lifestyle and prevent Type 2 Diabetes amongst South Asians with central obesity and prediabetes
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
(824989) EUCAN-Connect - A federated FAIR platform enabling large-scale analysis of high-value cohort data connecting Europe and Canada in personalized health
(279143) EPI-MIGRANT - Identification of epigenetic markers underlying increased risk of T2D in South Asians
(874739) LONGITOOLS - Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases
(848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity
Academy of Finland Grant Number: 322098
Detailed Information: 322098 (Academy of Finland Funding decision)
285547 (Academy of Finland Funding decision)
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