Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma
Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2013.04.032
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发表时间：
2013-09-01
影响因子：
25.7
通讯作者：
Bochud, Pierre-Yves
中科院分区：
文献类型：
--
作者：
Lange, Christian M.;Bibert, Stephanie;Bochud, Pierre-Yves
背景与目的：最近，一项全基因组关联研究（GWAS）发现MICA（先导单核苷酸多态性[SNP] rs2596542）的遗传变异与日本丙型肝炎病毒（HCV）相关的肝细胞癌（HCC）有关。在目前的研究中，我们试图确定这种SNP是否也能预测高加索人群中HCC的发展。方法：对来自瑞士丙型肝炎队列研究（SCCS）的1924例hcv感染患者的rs2596542附近的扩展区域进行基因分型。在日本和欧洲人群中计算了关键snp之间的成对相关性（HapMap3: CEU和JPT）。结果：令我们惊讶的是，MICA附近rs2596542的小等位基因A似乎对高加索人的HCC发展具有保护作用，与在日本人群中观察到的相反。详细的精细图谱分析显示，MICA上游HCP5 （rs2244546）的新SNP是SCCS中hcv相关HCC的强预测因子（单变量p = 0.027，多变量p = 0.0002，优势比= 3.96,95%置信区间= 1.90-8.27）。这个新发现的SNP在高加索人和日本人群中对HCC具有类似的直接影响，这表明rs2244546可能比最初发现的SNP更好地标记一个假定的真正变体。结论：我们的数据证实MICA/HCP5区域是hcv相关HCC的易感位点，并确定HCP5中的rs2244546是一个新的标记SNP。此外，我们的数据表明需要对不同种族的队列进行荟萃分析，以精细绘制GWAS信号。(C) 2013欧洲肝脏研究协会。Elsevier b.v.版权所有。
Background & Aims: Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identified by a genome-wide association study (GWAS) to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in Japanese patients. In the present study, we sought to determine whether this SNP is predictive of HCC development in the Caucasian population as well.Methods: An extended region around rs2596542 was genotyped in 1924 HCV-infected patients from the Swiss Hepatitis C Cohort Study (SCCS). Pair-wise correlation between key SNPs was calculated both in the Japanese and European populations (HapMap3: CEU and JPT).Results: To our surprise, the minor allele A of rs2596542 in proximity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse association as compared to the one observed in the Japanese population. Detailed fine-mapping analyses revealed a new SNP in HCP5 (rs2244546) upstream of MICA as strong predictor of HCV-related HCC in the SCCS (univariable p = 0.027; multivariable p = 0.0002, odds ratio = 3.96, 95% confidence interval = 1.90-8.27). This newly identified SNP had a similarly directed effect on HCC in both Caucasian and Japanese populations, suggesting that rs2244546 may better tag a putative true variant than the originally identified SNPs.Conclusions: Our data confirms the MICA/HCP5 region as susceptibility locus for HCV-related HCC and identifies rs2244546 in HCP5 as a novel tagging SNP. In addition, our data exemplify the need for conducting meta-analyses of cohorts of different ethnicities in order to fine map GWAS signals. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.