The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.
The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.
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DOI：
10.1053/j.gastro.2016.01.032
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发表时间：
2016-05
期刊：
影响因子：
29.4
通讯作者：
Romeo S
中科院分区：
文献类型：
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作者：
Mancina RM;Dongiovanni P;Petta S;Pingitore P;Meroni M;Rametta R;Borén J;Montalcini T;Pujia A;Wiklund O;Hindy G;Spagnuolo R;Motta BM;Pipitone RM;Craxì A;Fargion S;Nobili V;Käkelä P;Kärjä V;Männistö V;Pihlajamäki J;Reilly DF;Castro-Perez J;Kozlitina J;Valenti L;Romeo S
非酒精性脂肪性肝病（NAFLD）是肝损伤的主要原因，其特征在于脂肪变性。遗传因素会增加NAFLD的风险。一项全基因组关联研究表明，含有膜结合O-酰基转移酶结构域7基因（MBOAT 7，也称为LPIAT 1）和跨膜通道样4基因（TMC 4）的基因座中的rs641738 C>T变体增加了酒精滥用者肝硬化的风险。我们研究MBOAT 7/TMC 4是否是NAFLD发生和进展的易感基因座。我们对来自达拉斯心脏研究（达拉斯县居民的多种族人群概率样本）的3854名参与者和来自肝活检横断面队列的1149名欧洲个体的DNA进行了rs641738基因分型。收集临床和人体测量数据，并在参与者的血浆样本中测量生化和脂质组学。来自达拉斯心脏研究的总共2736名参与者也进行了质子磁共振波谱分析以测量肝脏甘油三酯含量。在肝活检横断面队列中，共有1149名个体接受了肝活检以诊断肝脏疾病和疾病严重程度。MBOAT 7/TMC 4基因座的基因型rs641738与2个队列中肝脂肪含量增加相关，并且与没有该变体的受试者相比，具有更严重的肝损伤和纤维化风险增加。发现MBOAT 7而不是TMC 4在肝脏中高度表达。MBOAT 7 rs641738 T等位基因与肝脏中较低的蛋白表达和与MBOAT 7功能降低一致的血浆磷脂酰肌醇种类的变化相关。我们提供了证据证明MBOAT 7 rs641738变体与欧洲血统个体NAFLD的发展和严重程度之间存在关联。这种关联似乎是介导的肝磷脂酰肌醇酰基链重塑的变化。
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. 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 underwent also 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. 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 to 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. 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.