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

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=6.9×10-6) 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 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 bloodderived 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.

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