A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease
Year: 2019
Type: article
Study design: Observational Study
Abstract: 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.
Source: Diabetes
DOI: 10.2337/db18-1193
Authors: Jiantao Ma, Jana Nano, Jingzhong Ding, Yinan Zheng, Rachel Hennein, Chunyu Liu, Elizabeth K. Speliotes, Tianxiao Huan, Ci Song, Michael M. Mendelson, Roby Joehanes, Michelle T. Long, Liming Liang, Jennifer A. Smith, Lindsay M. Reynolds, Mohsen Ghanbari, Taulant Muka, Joyce B.J. van Meurs, Louise J.M. Alferink, Oscar H. Franco, Abbas Dehghan, Scott Ratliff, Wei Zhao, Lawrence Bielak, Sharon L.R. Kardia, Patricia A. Peyser, Hongyan Ning, Lisa B. VanWagner, Donald M. Lloyd-Jones, John Jeffrey Carr, Philip Greenland, Alice H. Lichtenstein, Frank B. Hu, Yongmei Liu, Lifang Hou, Sarwa Darwish Murad, Daniel Levy
Institutions: Tufts University, National Institutes of Health, National Heart, Lung, and Blood Institute, Framingham Heart Study, Erasmus MC, Helmholtz Munich, German Center for Diabetes Research, Wake Forest University Health Sciences, Wake Forest University, Northwestern University, Boston University, University of Michigan, Uppsala University, Boston Children's Hospital, Harvard University, Mashhad University of Medical Sciences, MRC Centre for Environment and Health, Imperial College London, Vanderbilt University Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1080192134, G1141534940, MESA, G137869731, G1409423729, G1686417863, G1774001260, GENETIC DETERMINANTS OF HIGH BP IN THREE RACIAL GROUPS, G202194050, G2262782284, Circulating Epigenetic Biomarkers for Personalized Cardiovascular Disease Prevention, MESA, G275229112, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, G2953103934, G297113894, G316474162, G3647016462, G3687594596, MESA, Epigenome-Wide Association Study of DNA Methylation and Atherosclerosis, G3984593164, G399481048, Genetic Mechanisms of Arteriosclerosis in Hypertensive Sibships, G405311360, Dietary factors, biomarkers, metabolic pathways related to non-alcoholic fatty liver disease, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), G4512137732, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA, G5164707915, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, GENETIC DETERMINANTS OF HIGH BP IN THREE RACIAL GROUPS, G5787256936, CHARGE consortium: omics discovery for CVD and aging phenotypes, G6095866717, G6359107525, Institute for Clinical and Translational Research, Implementation science to improve cardiovascular outcomes among liver transplant recipients, The Framingham Heart Study, MESA, G6514094751, Epigenetic Biomarkers of Common Chronic Diseases, GENETIC DETERMINANTS OF HIGH BP IN THREE RACIAL GROUPS, Identification and functional impact of NAFLD associated genetic variants, MESA, NHLBI FAMILY BLOOD PRESSURE PROGRAM (GENOA), G7661673538, Longitudinal Changes in Pericardial Adiposity and Subclinical Atherosclerosis, Clinical and Translational Science Award, Predictors of Coronary Artery Calcification in an African-American Cohort, The Family Blood Pressure Program (GENOA Network), Diabetes Research Center (DRC)
OpenAlex ID: W2916486264