Genome-wide associationstudy to detect disease-associated genes in Japanese patients with primary biliary cirrhosis

为了确定日本人群原发性胆汁性肝硬化（PBC）的易感基因位点，对1327例PBC病例和1120例健康对照进行了全基因组关联研究（GWAS）和随后的重复研究。两个显着的非HLA易感性位点（TNFSF 15和POU 2AF 1）的PBC被确定。此外，在21个非HLA易感性位点中，有10个位点（CD 80、IKZF 3、IL 7 R、NFKB 1、STAT 4、CXCR 5、TNFAIP 2、MAP 3 K 7IP 1、rs6974491、DENND 1B）在欧洲血统的PBC中显示出显著的相关性。 这些结果表明两种疾病途径在欧洲血统和日本人群中的重要性，即T细胞（CD 80，IL 12 A，IL 12 RB 2，STAT 4，TNF 15）和B细胞（IL 7 R，CXCR 5，POU 2 AF 1，SPIB，IKZF 3）的Th 1/Th 17分化。此外，对肿瘤坏死因子15（TNFSF 15）编码的肿瘤坏死因子样配体1A（TL 1A）在外周血和局部表达的研究表明，TL 1A可能参与了PBC的发病机制。

To identify susceptibility loci for primary biliary cirrhosis(PBC) in Japanese population, a genome-wide association study (GWAS) and subsequent replication study were performed in a total of 1327 PBC cases and 1120 healthy controls. Two significant non-HLA susceptibility loci (TNFSF15 and POU2AF1) for PBC were identified. In addition, 10 loci (CD80, IKZF3, IL7R, NFKB1, STAT4, CXCR5, TNFAIP2, MAP3K7IP1, rs6974491, DENND1B) out of 21 non-HLA susceptibility loci for PBC in European descent showed significant associations in Japanese population. These results indicated the importance of two disease-pathways in both European descent and Japanese population, Th1/Th17 differentiation of T cells (CD80, IL12A, IL12RB2, STAT4, TNFSF15) and B cells(IL7R, CXCR5, POU2AF1, SPIB, IKZF3). In addition, the study for systemic and local expression of TNF-like ligand 1A (TL1A), which is encoded by TNFSF15, indicated that TL1A may be involved in the pathogenesis of PBC.