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

Monica del C. Gomez-Alonso; Anja Kretschmer; Rory Wilson; Liliane Pfeiffer; Ville Karhunen; Ilkka Seppälä; Weihua Zhang; Kirstin Mittelstraß; Simone Wahl; Pamela R. Matias-Garcia; Holger Prokisch; Sacha Horn; Thomas Meitinger; Luis R. Serrano-Garcia; Sylvain Sebert; Olli Raitakari; Marie Loh; Wolfgang Rathmann; Martina Müller-Nurasyid; Christian Herder; Michael Roden; Mikko Hurme; Marjo Riitta Jarvelin; Mika Ala-Korpela; Jaspal S. Kooner; Annette Peters; Terho Lehtimäki; John C. Chambers; Christian Gieger; Johannes Kettunen; Melanie Waldenberger

doi:10.1186/s13148-020-00957-8

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

Monica del C. Gomez-Alonso
, Anja Kretschmer
, Rory Wilson
, Liliane Pfeiffer
, Ville Karhunen
, Ilkka Seppälä
, Weihua Zhang
, Kirstin Mittelstraß
, Simone Wahl
, Pamela R. Matias-Garcia
, Holger Prokisch
, Sacha Horn
, Thomas Meitinger
, Luis R. Serrano-Garcia
, Sylvain Sebert
, Olli Raitakari
, Marie Loh
, Wolfgang Rathmann
, Martina Müller-Nurasyid
, Christian Herder

Michael Roden, Mikko Hurme, Marjo Riitta Jarvelin, Mika Ala-Korpela, Jaspal S. Kooner, Annette Peters, Terho Lehtimäki, John C. Chambers, Christian Gieger, Johannes Kettunen, Melanie Waldenberger^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

78 Citations (Scopus)

21 Downloads (Pure)

Abstract

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.

Original language	English
Article number	7
Journal	Clinical Epigenetics
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13148-020-00957-8
Publication status	Published - 2021
Publication type	A1 Journal article-refereed

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. CH received honoraria from Lilly and Sanofi and a research Grant from Sanofi outside the submitted work.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CpG site
Fatty acids
HDL
LDL
Lipoprotein composition
Lipoprotein sizes
Myocardial infarction
NMR
Obesity
VLDL

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Molecular Biology
Genetics
Developmental Biology
Genetics(clinical)

Access to Document

10.1186/s13148-020-00957-8Licence: CC BY

s13148-020-00957-8Final published version, 1.81 MBLicence: CC BY

http://urn.fi/URN:NBN:fi:tuni-202105265450Licence: CC BY

Additional file 15 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C. (Creator), Kretschmer, A. (Creator), Wilson, R. (Creator), Pfeiffer, L. (Creator), Karhunen, V. (Creator), Seppälä, I. (Creator), Zhang, W. (Contributor), Mittelstraß, K. (Creator), Wahl, S. (Creator), Matias-Garcia, P. R. (Creator), Prokisch, H. (Creator), Horn, S. (Creator), Meitinger, T. (Creator), Serrano-Garcia, L. R. (Creator), Sebert, S. (Creator), Raitakari, O. (Creator), Loh, M. (Creator), Rathmann, W. (Creator), Müller-Nurasyid, M. (Creator), Herder, C. (Creator), Roden, M. (Creator), Hurme, M. (Creator), Jarvelin, M.-R. (Contributor), Ala-Korpela, M. (Creator), Kooner, J. S. (Creator), Peters, A. (Creator), Lehtimäki, T. (Creator), Chambers, J. C. (Creator), Gieger, C. (Creator), Kettunen, J. (Creator) & Waldenberger, M. (Creator), figshare, 2021
DOI: 10.6084/m9.figshare.13545083.v1, https://springernature.figshare.com/articles/dataset/Additional_file_15_of_DNA_methylation_and_lipid_metabolism_an_EWAS_of_226_metabolic_measures/13545083/1
Dataset

Cite this

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., ... Waldenberger, M. (2021). DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures. Clinical Epigenetics, 13(1), Article 7. https://doi.org/10.1186/s13148-020-00957-8

@article{c26d4453078f450e814fbeb532934f58,

title = "DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures",

abstract = "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.",

keywords = "CpG site, Fatty acids, HDL, LDL, Lipoprotein composition, Lipoprotein sizes, Myocardial infarction, NMR, Obesity, VLDL",

author = "Gomez-Alonso, \{Monica del C.\} and Anja Kretschmer and Rory Wilson and Liliane Pfeiffer and Ville Karhunen and Ilkka Sepp{\"a}l{\"a} and Weihua Zhang and Kirstin Mittelstra{\ss} and Simone Wahl and Matias-Garcia, \{Pamela R.\} and Holger Prokisch and Sacha Horn and Thomas Meitinger and Serrano-Garcia, \{Luis R.\} and Sylvain Sebert and Olli Raitakari and Marie Loh and Wolfgang Rathmann and Martina M{\"u}ller-Nurasyid and Christian Herder and Michael Roden and Mikko Hurme and Jarvelin, \{Marjo Riitta\} and Mika Ala-Korpela and Kooner, \{Jaspal S.\} and Annette Peters and Terho Lehtim{\"a}ki and Chambers, \{John C.\} and Christian Gieger and Johannes Kettunen and Melanie Waldenberger",

note = "Funding Information: The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen – 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-Universit{\"a}t, 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; Yrj{\"o} 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{\textquoteright}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 Tecnolog{\'i}a (CONACyT)-M{\'e}xico. MAK was supported by a research Grant from the Sigrid Juselius Foundation, Finland. JC is supported by the Singapore Ministry of Health{\textquoteright}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. Funding Information: CH received honoraria from Lilly and Sanofi and a research Grant from Sanofi outside the submitted work. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2021",

doi = "10.1186/s13148-020-00957-8",

language = "English",

volume = "13",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "BioMed Central",

number = "1",

}

Gomez-Alonso, MDC, Kretschmer, A, Wilson, R, Pfeiffer, L, Karhunen, V, Seppälä, I, Zhang, W, Mittelstraß, K, Wahl, S, Matias-Garcia, PR, Prokisch, H, Horn, S, Meitinger, T, Serrano-Garcia, LR, Sebert, S, Raitakari, O, Loh, M, Rathmann, W, Müller-Nurasyid, M, Herder, C, Roden, M, Hurme, M, Jarvelin, MR, Ala-Korpela, M, Kooner, JS, Peters, A, Lehtimäki, T, Chambers, JC, Gieger, C, Kettunen, J & Waldenberger, M 2021, 'DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures', Clinical Epigenetics, vol. 13, no. 1, 7. https://doi.org/10.1186/s13148-020-00957-8

TY - JOUR

T1 - DNA methylation and lipid metabolism

T2 - an EWAS of 226 metabolic measures

AU - Gomez-Alonso, Monica del C.

AU - Kretschmer, Anja

AU - Wilson, Rory

AU - Pfeiffer, Liliane

AU - Karhunen, Ville

AU - Seppälä, Ilkka

AU - Zhang, Weihua

AU - Mittelstraß, Kirstin

AU - Wahl, Simone

AU - Matias-Garcia, Pamela R.

AU - Prokisch, Holger

AU - Horn, Sacha

AU - Meitinger, Thomas

AU - Serrano-Garcia, Luis R.

AU - Sebert, Sylvain

AU - Raitakari, Olli

AU - Loh, Marie

AU - Rathmann, Wolfgang

AU - Müller-Nurasyid, Martina

AU - Herder, Christian

AU - Roden, Michael

AU - Hurme, Mikko

AU - Jarvelin, Marjo Riitta

AU - Ala-Korpela, Mika

AU - Kooner, Jaspal S.

AU - Peters, Annette

AU - Lehtimäki, Terho

AU - Chambers, John C.

AU - Gieger, Christian

AU - Kettunen, Johannes

AU - Waldenberger, Melanie

N1 - Funding Information: 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. Funding Information: CH received honoraria from Lilly and Sanofi and a research Grant from Sanofi outside the submitted work. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - CpG site

KW - Fatty acids

KW - HDL

KW - LDL

KW - Lipoprotein composition

KW - Lipoprotein sizes

KW - Myocardial infarction

KW - NMR

KW - Obesity

KW - VLDL

U2 - 10.1186/s13148-020-00957-8

DO - 10.1186/s13148-020-00957-8

M3 - Article

AN - SCOPUS:85098891467

SN - 1868-7075

VL - 13

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 7

ER -

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

Abstract

Funding

UN SDGs

Keywords

Publication forum classification

ASJC Scopus subject areas

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Additional file 15 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

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