A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease.

Journal Article (Journal Article)

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 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 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.

Full Text

Duke Authors

Cited Authors

  • Ma, J; Nano, J; Ding, J; Zheng, Y; Hennein, R; Liu, C; Speliotes, EK; Huan, T; Song, C; Mendelson, MM; Joehanes, R; Long, MT; Liang, L; Smith, JA; Reynolds, LM; Ghanbari, M; Muka, T; van Meurs, JBJ; Alferink, LJM; Franco, OH; Dehghan, A; Ratliff, S; Zhao, W; Bielak, L; Kardia, SLR; Peyser, PA; Ning, H; VanWagner, LB; Lloyd-Jones, DM; Carr, JJ; Greenland, P; Lichtenstein, AH; Hu, FB; Liu, Y; Hou, L; Darwish Murad, S; Levy, D

Published Date

  • May 2019

Published In

Volume / Issue

  • 68 / 5

Start / End Page

  • 1073 - 1083

PubMed ID

  • 30936141

Pubmed Central ID

  • PMC6477898

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

Digital Object Identifier (DOI)

  • 10.2337/DB18-1193


  • eng

Conference Location

  • United States