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A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease
NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Tufts Univ, Nutr Data Sci, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, Neuherberg, Germany;German Ctr Diabet Res, Munich, Germany.
Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
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2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 5, p. 1073-1083Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC , 2019. Vol. 68, no 5, p. 1073-1083
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Endocrinology and Diabetes Medical Genetics
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URN: urn:nbn:se:uu:diva-383842DOI: 10.2337/DB18-1193ISI: 000466756900022PubMedID: 30936141OAI: oai:DiVA.org:uu-383842DiVA, id: diva2:1318034
Available from: 2019-05-24 Created: 2019-05-24 Last updated: 2019-05-24Bibliographically approved

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