TY - JOUR
T1 - A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease
AU - Ma, Jiantao
AU - Nano, Jana
AU - Ding, Jingzhong
AU - Zheng, Yinan
AU - Hennein, Rachel
AU - Liu, Chunyu
AU - Speliotes, Elizabeth K.
AU - Huan, Tianxiao
AU - Song, Ci
AU - Mendelson, Michael M.
AU - Joehanes, Roby
AU - Long, Michelle T.
AU - Liang, Liming
AU - Smith, Jennifer A.
AU - Reynolds, Lindsay M.
AU - Ghanbari, Mohsen
AU - Muka, Taulant
AU - Van Meurs, Joyce B.J.
AU - Alferink, Louise J.M.
AU - Franco, Oscar H.
AU - Dehghan, Abbas
AU - Ratliff, Scott
AU - Zhao, Wei
AU - Bielak, Lawrence
AU - Kardia, Sharon L.R.
AU - Peyser, Patricia A.
AU - Ning, Hongyan
AU - VanWagner, Lisa B.
AU - Lloyd-Jones, Donald M.
AU - Carr, John Jeffrey
AU - Greenland, Philip
AU - Lichtenstein, Alice H.
AU - Hu, Frank B.
AU - Liu, Yongmei
AU - Hou, Lifang
AU - Murad, Sarwa Darwish
AU - Levy, Daniel
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 DNAmethylation signatures of NAFLD across racial/ethnic groups.
AB - 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 DNAmethylation signatures of NAFLD across racial/ethnic groups.
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U2 - 10.2337/DB18-1193
DO - 10.2337/DB18-1193
M3 - Article
C2 - 30936141
AN - SCOPUS:85065112934
VL - 68
SP - 1073
EP - 1083
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 5
ER -