Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1
Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1
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DOI：
10.1053/j.gastro.2020.06.014
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发表时间：
2020-10-01
期刊：
影响因子：
29.4
通讯作者：
Stickel, Felix
中科院分区：
文献类型：
--
作者：
Innes, Hamish;Buch, Stephan;Stickel, Felix
背景和目的：对影响酒精性肝硬化发展的遗传因素知之甚少。我们对来自英国生物库（UKB）的样本进行了全基因组关联研究（GWAS），以确定与酒精相关肝病风险相关的多态性。方法：我们对UKB的35，839名参与者进行了GWAS，这些参与者摄入大量酒精，以对抗肝纤维化标志物（FIB-4，APRI和Forns指数评分）和肝细胞损伤（转氨酶水平）。在3个独立的欧洲队列（I期验证队列; n=2545）中，检测发现分析中鉴定的基因座与酒精相关性肝硬化的相关性。与酒精相关肝硬化相关的变异体在验证中的错误发现率低于20%，然后在2个额外的欧洲验证队列中直接进行基因分型（2期验证，n=2068）。结果：在发现队列的GWAS中，我们确定了50个具有全基因组显著性的独立风险位点（P < 5 x 10（-8））。在1期验证队列中，这些位点中有9个与酒精相关肝硬化显著相关;在2期验证队列中，这9个位点中有6个与酒精相关肝硬化显著相关，错误发现率低于5%。这些位点包括线粒体偕胺肟还原组分1基因（MARC 1）和异质核核糖核蛋白U样1基因（HNRNPUL 1）的变异体。在2期验证队列中调整年龄、性别、体重指数和2型糖尿病后，MARC 1：rs 2642438的次要A等位基因与酒精相关性肝硬化风险降低相关（调整后比值比，0.76; P=.0027）;相反，HNRNPUL 1：rs 15052的次要C等位基因与酒精相关性肝硬化风险增加相关（调整后比值比，1.30; P=.020）。结论：在来自UKB的样本的GWAS中，我们确定并验证了（在5个欧洲队列中）单核苷酸多态性，这些多态性以相反的方向影响酒精相关性肝硬化的风险：MARC 1：rs 2642438中的次要A等位基因降低风险，而HNRNPUL 1：rs 15052中的次要C等位基因增加风险。
BACKGROUND AND AIMS: Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease. METHODS: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068). RESULTS: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 x 10(-8)). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020). CONCLUSIONS: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.