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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #362701

Research Project: Cardiovascular Nutrition and Health

Location: Jean Mayer Human Nutrition Research Center On Aging

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

item Ma, Jiantao - National Institutes Of Health (NIH)
item Nano, Jana - Helmholtz Centre
item Ding, Jingzhong - Wake Forest University
item Zheng, Yinan - Northwestern University
item Hennein, Rachel - National Institutes Of Health (NIH)
item Liu, Chunyu - Boston University
item Speliotes, Elizabeth - University Of Michigan
item Huan, Tianxiao - National Institutes Of Health (NIH)
item Song, Ci - National Institutes Of Health (NIH)
item Mendelson, Michael - Boston Children'S Hospital
item Joehanes, Roby - National Institutes Of Health (NIH)
item Long, Michelle - Boston University
item Liang, Liming - Harvard University
item Smith, Jennifer - University Of Michigan
item Reynolds, Lindsay - Wake Forest University
item Ghanbari, Mohsen - Erasmus Medical Center
item Muka, Taulant - University Of Bern
item Van Meurs, Joyce - Erasmus Medical Center
item Alferink, Louise - Erasmus Medical Center
item Franco, Oscar - Erasmus Medical Center
item Dehghan, Abbas - Imperial College
item Ratliff, Scott - University Of Michigan
item Zhao, Wei - University Of Michigan
item Bielak, Lawrence - University Of Michigan
item Kardia, Sharon - University Of Michigan
item Peyser, Patricia - University Of Michigan
item Ning, Hongyan - Northwestern University
item Vanwagner, Lisa - Northwestern University
item Lloyd-jones, Donald - Northwestern University
item Carr, John Jeffrey - Vanderbilt University
item Greenland, Philip - Northwestern University
item Lichtenstein, Alice - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Hu, Frank - Harvard University
item Liu, Yongmei - Wake Forest University
item Hou, Lifang - Northwestern University
item Murad, Sarwa - Erasmus Medical Center
item Levy, Daniel - National Institutes Of Health (NIH)

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/1/2019
Publication Date: 2/1/2019
Citation: 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., Ghanbari, M., Muka, T., Van Meurs, J., Alferink, L.J., Franco, O.H., Dehghan, A., Ratliff, S., Zhao, W., Bielak, L., Kardia, S.L., Peyser, P.A., Ning, H., Vanwagner, L.B., Lloyd-Jones, D.M., Carr, J., Greenland, P., Lichtenstein, A.H., Hu, F.B., Liu, Y., Hou, L., Murad, S.D., Levy, D. 2019. A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for non-alcoholic fatty liver disease. Diabetes.

Interpretive Summary: There is substantial evidence linking cardiovascular disease and nonalcoholic fatty liver disease (elevated hepatic fat). This is of particular concern because the prevalence of nonalcoholic fatty liver disease is increasing, fueled in part by the obesity epidemic. Our aim was to determine whether differences in a blood measure, DNA methylation signatures, was associated with hepatic fat content, and hence, could be used as a biomarker for elevated risk of developing nonalcoholic fatty liver disease and subsequent cardiovascular disease. Hepatic fat content was determined in four population-based cohort studies using either ultrasound imaging or computed tomography. DNA methylation was assessed using a commercial array. The resulting data identified a unique DNA methylation pattern related to hepatic fat. Also identified were several hepatic fat-associated signals that may be biomarkers for new-onset type 2 diabetes. These data demonstrates that a peripheral blood-derived DNA methylation signature is associated with hepatic fat accumulation.

Technical Abstract: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes. 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 over 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=6.9x10^-6) with replication at Bonferroni corrected p<8.6x10^-4. Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (p=2.5x10^-4). Hypomethylation of the same CpG was also associated with risk for new-onset type 2 diabetes (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 type 2 diabetes. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups. The estimated global prevalence of nonalcoholic fatty liver disease (NAFLD) in adults is 24% and has increased substantially along with the increasing rates of obesity (1). NAFLD correlates with increased risk of type 2 diabetes (T2D) (2), and it is the second leading contributor to hepatic failure necessitating transplantation (3). A prior study in three family-based cohorts estimated the heritability of hepatic steatosis to be 27%; however, common genetic variants from genome-wide association studies (GWAS) account for less than five percent of interindividual variance in hepatic fat (4). Epigenetics may explain part of the inter-individual variance of steatosis. Several studies have demonstrated altered DNA methylation profiles in liver biopsy samples collected from individuals with NAFLD (5; 6). One study showed that peripheral blood-derived DNA hypermethylation at one cytosine-guanine dinucleotide (CpG; cg06690548) located in an intron of SLC7A11 may be associated with a lower risk of steatosis (7). In general, however, prior studies were limited by small sample sizes to discover DNA methylation sites associated with hepatic fat accumulation. To bridge this knowledge gap, we examined the epigenome-wide association between DNA methylation at over 400,000 CpGs and hepatic fat in European ancestry (EA), African ancestry (AA), and Hispanic ancestry (HA) participants from five population-based cohort studies with hepatic fat measurements derived from noninvasive imaging. For hepatic fat-associated CpGs, we further examined their relations to genetic variants, gene expression, and regulatory functions, and explored potential relations of DNA methylation to NAFLD and T2D.