Genome-wide Association Study Identifies TNFSF15 and POU2AF1 as Susceptibility Loci for Primary Biliary Cirrhosis in the Japanese Population
Genome-wide Association Study Identifies TNFSF15 and POU2AF1 as Susceptibility Loci for Primary Biliary Cirrhosis in the Japanese Population
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DOI：
10.1016/j.ajhg.2012.08.010
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发表时间：
2012-10-05
影响因子：
9.8
通讯作者：
Ishibashi, Hiromi
中科院分区：
文献类型：
--
作者：
Nakamura, Minoru;Nishida, Nao;Ishibashi, Hiromi
为了鉴定原发性二元肝硬化（PBC）的易感基因座，在963名日本人（487例PBC病例和476名健康对照）中进行了全基因组关联研究（GWAS），并在随后的复制研究中包括1，402名其他日本人（787例病例和615名对照）。除了最重要的易感区域，人类白细胞抗原（HLA），我们确定了两个重要的易感基因座，TNFSF 15（rs 4979462）和POU 2AF 1（rs 4938534）（rs 4979462的合并比值比[OR] = 1.56，p = 2.84 x 10（-14），rs 4938534的合并OR = 1.39，p = 2.38 x 10（-8））。在21个非HLA易感性PBC基因座中，在欧洲血统个体的GWAS中鉴定了三个基因座，（IL 7 R，IKZF 3和CD 80）显示出显著的相关性（合并p = 3.66 x 10（-8）、3.66 x 10（-9）和3.04 x 10（-9），STAT 4和NFKB 1基因座显示与日本人群PBC有关联（合并p值分别为1.11 x 10（-6）和1.42 x 10（-7））。这些观察结果表明，PBC的遗传易感性位点存在种族差异，TNF信号传导和B细胞分化对欧洲血统和日本个体PBC的发展具有重要意义。
For the identification of susceptibility loci for primary binary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 x 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 x 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 x 10(-8), 3.66 x 10(-9), and 3.04 x 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 x 10(-6) and 1.42 x 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.