• Jana Nano, Mohsen Ghanbari, Wenshi Wang, Paul S de Vries, Klodian Dhana, Taulant Muka, André G Uitterlinden, van Meurs Joyce B J JBJ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands., Albert Hofman, BIOS consortium, Oscar H Franco, Qiuwei Pan, Murad Sarwa Darwish SD Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands., and Abbas Dehghan.
• Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
• Gastroenterology. 2017 Oct 1; 153 (4): 1096-1106.e2.

Background & AimsEpigenetic mechanisms might be involved in the regulation of liver enzyme level. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of liver enzymes and hepatic steatosis.MethodsWe conducted an epigenome-wide association study in whole blood for liver enzyme levels, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), among a discovery set of 731 participants of the Rotterdam Study and sought replication in a non-overlapping sample of 719 individuals. Significant DNA methylation changes were further analyzed to evaluate their relation with hepatic steatosis. Expression levels of the top identified gene were measured in 9 human liver cell lines and compared with expression profiles of its potential targets associated with lipid traits. The candidate gene was subsequently knocked down in human hepatoma cells using lentiviral vectors expressing small hairpin RNAs.ResultsEight probes annotated to SLC7A11, SLC1A5, SLC43A1, PHGDH, PSORS1C1, SREBF1, ANKS3 were associated with GGT and 1 probe annotated to SLC7A11 was associated with ALT after Bonferroni correction (1.0 × 10-7). No probe was identified for AST levels. Four probes for GGT levels including cg06690548 (SLC7A11), cg11376147 (SLC43A1), cg22304262 (SLC1A5), and cg14476101 (PHGDH), and 1 for ALT cg06690548 (SLC7A11) were replicated. DNA methylation at SLC7A11 was associated with reduced risk of hepatic steatosis in participants (odds ratio, 0.69; 95% CI= 0.55-0.93; P value: 2.7 × 10-3). In functional experiments, SLC7A11 was highly expressed in human liver cells; its expression is positively correlated with expression of a panel of lipid-associated genes, indicating a role of SLC7A11 in lipid metabolism.ConclusionsOur results provide new insights into epigenetic mechanisms associated with markers of liver function and hepatic steatosis, laying the groundwork for future diagnostic and therapeutic applications.Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

53 keywords...

hide…