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Ma, J.* ; Nano, J. ; Ding, J.* ; Zheng, Y.* ; Hennein, R.* ; Liu, C.* ; Speliotes, E.K.* ; Huan, T.* ; Song, C.* ; Mendelson, M.M.* ; Joehanes, R.* ; Long, M.T.* ; Liang, L.* ; Smith, J.A.* ; Reynolds, L.M.* ; Ghanbari, M.* ; Muka, T.* ; van Meurs, J.B.J.* ; Alferink, L.J.M.* ; Franco, O.H.* ; Dehghan, A.* ; Ratliff, S.* ; Zhao, W.* ; Bielak, L.F.* ; Kardia, S.L.R.* ; Peyser, P.A.* ; Ning, H.* ; VanWagner, L.B.* ; Lloyd-Jones, D.M.* ; Carr, J.J.* ; Greenland, P.* ; Lichtenstein, A.H.* ; Hu, F.B.* ; Liu, Y.* ; Hou, L.* ; Darwish Murad, S.* ; Levy, D.*

A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for non-alcoholic fatty liver disease.

Diabetes 68, 1073-1083 (2019)

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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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