Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
Bibliographical noteFunding Information:
We thank our Amish community and research volunteers for their long-standing partnership in research, and acknowledge the dedication of our Amish liaisons, field workers and the Amish Research Clinic staff, without which these studies would not have been possible. We thank the staff and participants of the ARIC study for their important contributions. We would also like to thank the families that participated in the GENOA study. The authors are grateful to the Rotterdam Study participants, the staff involved with the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. We thank Mr. Michael Verbiest, Ms. Mila Jhamai, Ms. Sarah Higgins, Mr. Marijn Verkerk, and Lisette Stolk PhD for their help in creating the methylation database. We thank Ms. Mila Jhamai, Ms. Sarah Higgins, Marjolein Peters, MSc, Mr. Marijn Verkerk and Jeroen van Rooij, MSc for their help in creating the RNA array expression database. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). Funding was also supported by 5RC2HL102419 and R01NS087541. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL092111, R01HL105756, R01HL103612, R01HL111089, R01HL116747, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA) as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health and an NIH Director’s Challenge Award (D. Levy, Principal Investigator). The GOLDN epigenetics study is funded by the NIH National Heart, Lung, and Blood Institute grant R01 HL104135-01. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (HL054457, HL100185, HL119443, and HL133221) of the National Institutes of Health. 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 was 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. The TwinsUK epigenetic study received support from the ESRC (ES/N000404/1). The TwinsUK study funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007–2013); National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. SNP genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The PIVUS study was supported by Swedish Research Council (Grant no. 2012-1397), Knut och Alice Wallenberg Foundation (Grant no. 2013.0126), Swedish Heart-Lung Foundation (grant no. 20140422), and Swedish Diabetes Foundation (Grant no. 2013-024). The Rotterdam Study EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The generation and management of RNA-expression array data for the Rotterdam Study was executed and funded by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The Women’s Health Initiative data, WHI-BA23 and WHI-EMPC, were generated through an NHLBI Broad Agency Announcement contract (HHSN268201300006C) and a National Institute of Environmental Health Sciences grant (R01-ES020836). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.
Alan R Shuldiner is an employee of Regeneron Pharmaceuticals, Inc. Bruce M Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Kim Valeska Emilie Braun works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc. and AXA.
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