Genome-Wide Association Study of NAFLD Using Electronic Health Records.
Genome-Wide Association Study of NAFLD Using Electronic Health Records.
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DOI：
10.1002/hep4.1805
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发表时间：
2022-03
影响因子：
5.1
通讯作者：
Spiliopoulou A
中科院分区：
文献类型：
--
作者：
Fairfield CJ;Drake TM;Pius R;Bretherick AD;Campbell A;Clark DW;Fallowfield JA;Hayward C;Henderson NC;Joshi PK;Mills NL;Porteous DJ;Ramachandran P;Semple RK;Shaw CA;Sudlow CLM;Timmers PRHJ;Wilson JF;Wigmore SJ;Harrison EM;Spiliopoulou A
全基因组关联研究（GWAS）已经确定了非酒精性脂肪肝（NAFLD）的几个风险位点。以前的研究在很大程度上依赖于小样本量，并评估了数量性状。我们在英国生物库中使用基于最近共识指南中推荐的诊断代码的NAFLD记录诊断进行了病例对照GWAS。我们对4，761例NAFLD患者和373，227例无NAFLD证据的健康对照者进行了GWAS。进行敏感性分析，排除其他共存的肝脏病理，调整体重指数（BMI）和酒精摄入量。通过logistic回归对年龄、性别、遗传主成分和基因分型批次进行调整，共评估了9，723，654个变异体。我们使用可用的汇总关联统计量进行了GWAS Meta分析。确定了6个风险位点（P < 5*10−8）（载脂蛋白E [APOE]、含马铃薯糖蛋白样磷脂酶结构域3 [PNPLA 3]、跨膜6超家族成员2 [TM 6SF 2]、葡萄糖激酶调节因子[GCKR]、线粒体偕胺肟还原组分1 [MARC 1]和tribbles假激酶1 [TRIB 1]）。在敏感性分析中，所有位点均保持显著性，不存在共存的肝脏病理学，并且在校正BMI后。PNPLA 3和TM 6SF 2在调整酒精后仍然显着（只有158，388人知道酒精摄入量），其他人表现出一致的方向和影响程度。所有6个位点在Meta分析中均具有显著性。Rs 429358（P = 2.17*10−11）是APOE基因内的错义变异体，决定了APOE基因的等位基因Rs 429358与APOE基因的等位基因Rs 429358。APOE的α 4等位基因提供了针对NAFLD的保护（杂合子的比值比为0.84 [95%置信区间0.78 - 0.90]，纯合子为0.64 [0.50 - 0.79]）。结论：该GWAS复制了六个已知的NAFLD易感基因座，并证实了APOE的E14等位基因与NAFLD的保护作用相关。结果与使用NAFLD的组织学和放射学测量的已发表GWAS一致，证实通过共识指南的诊断代码识别的NAFLD是更具侵入性和昂贵方法的有效替代方案。
Genome‐wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case‐control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co‐existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta‐analysis using available summary association statistics. Six risk loci were identified (P < 5*10−8) (apolipoprotein E [APOE], patatin‐like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co‐existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta‐analysis. Rs429358 (P = 2.17*10−11) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78‐0.90] and homozygotes 0.64 [0.50‐0.79]). Conclusion: This GWAS replicates six known NAFLD‐susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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DOI：
10.1002/hep.31726
发表时间：
2021-07
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hagström H;Adams LA;Allen AM;Byrne CD;Chang Y;Grønbaek H;Ismail M;Jepsen P;Kanwal F;Kramer J;Lazarus JV;Long MT;Loomba R;Newsome PN;Rowe IA;Ryu S;Schattenberg JM;Serper M;Sheron N;Simon TG;Tapper EB;Wild S;Wong VW;Yilmaz Y;Zelber-Sagi S;Åberg F
通讯作者：
Åberg F
影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
29.4
作者：
Chalasani N;Guo X;Loomba R;Goodarzi MO;Haritunians T;Kwon S;Cui J;Taylor KD;Wilson L;Cummings OW;Chen YD;Rotter JI;Nonalcoholic Steatohepatitis Clinical Research Network
通讯作者：
Nonalcoholic Steatohepatitis Clinical Research Network
影响因子：
24.5
作者：
Dufour, Jean-Francois;Caussy, Cyrielle;Loomba, Rohit
通讯作者：
Loomba, Rohit