The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent

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• 作者：Rosellina Margherita Mancina¹ ; ^&lowast ; ; Paola Dongiovanni² ; ^&lowast ; ; Salvatore Petta³ ; Piero Pingitore¹ ; Marica Meroni⁴ ; Raffaela Rametta⁴ ; Jan Boré ; n¹ ; Tiziana Montalcini⁵ ; Arturo Pujia⁵ ; Olov Wiklund¹ ; ⁶ ; George Hindy⁷ ; Rocco Spagnuolo⁸ ; Benedetta Maria Motta¹ ; Rosaria Maria Pipitone⁴ ; Antonio Craxì ; ³ ; Silvia Fargion² ; ⁴ ; Valerio Nobili⁹ ; Pirjo Kä ; kelä ; ¹⁰ ; Vesa Kä ; rjä ; ¹¹ ; Ville Mä ; nnist&ouml ; ¹² ; Jussi Pihlajamä ; ki¹³ ; ¹⁴ ; Dermot F. Reilly¹⁵ ; Jose Castro-Perez¹⁶ ; ¹⁷ ; Julia Kozlitina¹⁸ ; ^{Julia.Kozlitina@UTSouthwestern.edu" class="auth_mail" title="E-mail the corresponding author} ; Luca Valenti² ; ⁴ ; ^{luca.valenti@unimi.it" class="auth_mail" title="E-mail the corresponding author} ; Stefano Romeo¹ ; ⁵ ; ⁶ ; ^{stefano.romeo@wlab.gu.se" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PNPLA3 ; TM6SF2 ; NASH ; Arachidonic Acid
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：150
• 期：5
• 页码：1219-1230.e6
• 全文大小：1851 K

文摘

Nonalcoholic 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.

Methods

We 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.

Results

The 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.

Conclusions

We 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.