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MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C.

ABSTRACT: Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.

SUBMITTER: Thabet K

PROVIDER: S-EPMC5027609 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C.

Thabet Khaled K Asimakopoulos Anastasia A Shojaei Maryam M Romero-Gomez Manuel M Mangia Alessandra A Irving William L WL Berg Thomas T Dore Gregory J GJ Grønbæk Henning H Sheridan David D Abate Maria Lorena ML Bugianesi Elisabetta E Weltman Martin M Mollison Lindsay L Cheng Wendy W Riordan Stephen S Fischer Janett J Spengler Ulrich U Nattermann Jacob J Wahid Ahmed A Rojas Angela A White Rose R Douglas Mark W MW McLeod Duncan D Powell Elizabeth E Liddle Christopher C van der Poorten David D George Jacob J Eslam Mohammed M

Nature communications 20160915

Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibros ...[more]

PMID: 27630043

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Project description:Background & aimsNonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD.MethodsWe genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity.ResultsThe genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function.ConclusionsWe provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

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MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C.

Publications

MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C.

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