全基因组关联分析荟萃鉴定出与非酒精性脂肪肝病相关的17个位点。
Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.
发表日期：2023 Sep 14
作者：
Yanhua Chen, Xiaomeng Du, Annapurna Kuppa, Mary F Feitosa, Lawrence F Bielak, Jeffrey R O'Connell, Solomon K Musani, Xiuqing Guo, Bratati Kahali, Vincent L Chen, Albert V Smith, Kathleen A Ryan, Gudny Eirksdottir, Matthew A Allison, Donald W Bowden, Matthew J Budoff, John Jeffrey Carr, Yii-Der I Chen, Kent D Taylor, Antonino Oliveri, Adolfo Correa, Breland F Crudup, Sharon L R Kardia, Thomas H Mosley, Jill M Norris, James G Terry, Jerome I Rotter, Lynne E Wagenknecht, Brian D Halligan, Kendra A Young, John E Hokanson, George R Washko, Vilmundur Gudnason, Michael A Province, Patricia A Peyser, Nicholette D Palmer, Elizabeth K Speliotes
来源：
NATURE GENETICS
摘要：
非酒精性脂肪性肝病（NAFLD）是一种常见且部分遗传性的疾病，目前尚无有效治疗方法。我们进行了一个全基因组关联研究（GWAS）荟萃分析，包括成像测量（n = 66,814）和诊断编码测量（3,584例病例对比621,081例对照）的不同祖源的NAFLD。我们在扭转家族1成员B（TOR1B）、脂肪质量和肥胖相关（FTO）、cordon-bleu WH2重复蛋白类似物1（COBLL1）/生长因子受体结合蛋白14（GRB14）、胰岛素受体（INSR）、甾醇调节元件结合转录因子1（SREBF1）和类油酸脂酶结构域蛋白2（PNPLA2）等基因中鉴定到与NAFLD相关的变异，同时对于甾醇调节元件结合转录因子3（PNPLA3）、跨膜6超家族2（TM6SF2）、载脂蛋白E（APOE）、葡萄糖激酶调节蛋白（GCKR）、tribbles同源物1（TRIB1）、甘油-3-磷酸酰基转移酶（GPAM）、线粒体成分1（MARC1）、微粒体三酰甘油转运蛋白大亚基（MTTP）、酒精脱氢酶1B（ADH1B）、跨膜通道类似4（TMC4）/膜结合O-酰转移酶结构域含7（MBOAT7）和受体型酪氨酸蛋白磷酸酶δ（PTPRD）等已被验证的与NAFLD相关的变异，强调线粒体、胆固醇和新生脂肪的贡献于NAFLD易感性。表型关联研究（PheWAS）分析表明，至少存在七种不同亚型的NAFLD。遗传风险在前10%和1%的个体中可使NAFLD、肝硬化和肝细胞癌的风险增加2.5倍到6倍。这些遗传变异可用于鉴定NAFLD的亚型、改进疾病风险评估，并且可指导针对性治疗的开发。© 2023. 作者授权给Springer Nature America, Inc. 版权所有。
Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.