Variants in the LGALS9 Gene Are Associated With Development of Liver Disease in Heavy Consumers of Alcohol.
Variants in the LGALS9 Gene Are Associated With Development of Liver Disease in Heavy Consumers of Alcohol.
复制标题
LGALS9 基因的变异与大量饮酒者患肝病有关。
DOI：
10.1016/j.cgh.2015.11.005
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Day,ChristopherP
中科院分区：
文献类型：
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作者：
Rosen,HugoR;Golden-Mason,Lucy;Daly,AnnK;Yang,Ivana;Day,ChristopherP
背景和目的酒精消费是慢性肝病的主要原因，并导致全球大部分酒精中毒相关死亡。然而，只有一小部分重度饮酒者会发展为晚期酒精性肝病（ALD），因此可能还有其他风险因素。我们调查是否在基因编码的半乳糖凝集素-9（LGALS 9），以前被证明介导肝损伤的多态性，与发展的ALD.MethodsWe分离的DNA从外周血单核细胞（PBMC）的575个人有风险的酒精消费，但没有其他危险因素的慢性肝病;所有的受试者都是白色欧洲人谁消耗了超过80克乙醇，每天。在受试者中，388例有ALD（包括268例肝硬化和74例酒精性肝炎;平均年龄49岁; 72%男性），187例肝功能正常，无生化或临床肝病证据（对照组;平均年龄42岁; 73%男性）。使用等位基因区分法对SelectLGALS 9多态性进行基因分型。我们还基因分型和测量的表达LGALS 9信使RNA在PBMC中的个人谁不是重度消费者的alcohol.ResultsWe使用的数据从HapMap项目，以确定5个单核苷酸多态性（SNP）标记所有常见的单倍型。当我们在患有肝病的个体与没有肝病的个体中寻找这些SNPs时，4个（rs3751093，rs 4239242，rs732222和rs 4794976）与发生ALD的风险增加相关。我们发现LGALS 9 mRNA和蛋白的表达水平与PBMC携带的等位基因相关。多变量分析证实，rs 4239242和rs 4794976与ALD的风险增加。虽然需要更大规模的研究，但这些信息可用于确定个体发展ALD的风险或开发治疗药物。
Background & AimsAlcohol consumption is a major cause of chronic liver disease and contributes to a large proportion of cirrhosis-related deaths worldwide. However, only a fraction of heavy consumers of alcohol develop advanced alcoholic liver disease (ALD), so there are likely to be other risk factors. We investigated whether polymorphisms in the gene encoding galectin-9 (LGALS9), previously shown to mediate liver injury, were associated with the development of ALD.MethodsWe isolated DNA from peripheral blood mononuclear cells (PBMCs) of 575 individuals with at-risk alcohol consumption but no other risk factors for chronic liver disease; all subjects were white Europeans who had consumed more than 80 grams ethanol per day. Of the subjects, 388 had ALD (including, 268 with cirrhosis and 74 with alcoholic hepatitis; mean age, 49 y; 72% male) and 187 had normal liver function with no biochemical or clinical evidence of liver disease (controls; mean age, 42 y; 73% male). SelectLGALS9polymorphisms were genotyped using allelic discrimination. We also genotyped and measured expression ofLGALS9messenger RNA in PBMCs from individuals who were not heavy consumers of alcohol.ResultsWe used data from the HapMap project to identify 5 single-nucleotide polymorphisms (SNPs) that tag all the common haplotypes. When we looked for these SNPs in individuals with vs without liver disease, 4 (rs3751093, rs4239242, rs732222, and rs4794976) were associated with an increased risk of developing ALD. We found that levels ofLGALS9messenger RNA and protein expressed were associated with an allele carried by PBMCs. Multivariate analysis confirmed that rs4239242 and rs4794976 were associated with an increased risk of ALD.ConclusionsIn a genetic analysis of heavy consumers of alcohol, we associated 2 SNPS inLGALS9with the development of ALD. Although larger studies are required, this information could be used to determine the risk of individuals developing ALD or to develop therapeutic agents.