Journal
DIABETES
Volume 68, Issue 5, Pages 1073-1083Publisher
AMER DIABETES ASSOC
DOI: 10.2337/DB18-1193
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Categories
Funding
- National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) [R01-HL-105756]
- Intramural Research Program of the NIH: NHLBI
- National Institute on Aging (NIA)
- National Institute of Environmental Health Sciences
- NIH contract [N01-HC-25195]
- Division of Intramural Research, NHLBI, NIH, Bethesda, MD
- Division of Intramural Research, NHLBI
- Center for Information Technology, NIH
- Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center
- Netherlands Organization for Scientific Research (NWO) [184021007]
- Erasmus University Medical Center, Rotterdam
- Erasmus University, Rotterdam
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (Directorate-General XII)
- Municipality of Rotterdam
- NHLBI
- MESA
- NIH [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, DK063491]
- NIA [1R01HL101250-01]
- NHLBI [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C, R01-HL098445, K23-HL-136891]
- American Heart Association [17SFRN33700278, 14SFRN20790000]
- NHLBI of the NIH [HL-054464, HL-054457, HL-054481, HL-100185, HL-119443, HL-085571, HL-133221]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006001] Funding Source: NIH RePORTER
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Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 x 10(-6)) with replication at Bonferroni-corrected P < 8.6 x 10(-4). Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 10(-4)). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.
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