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

为了确定日本人群中原发性胆汁性肝硬变(PBC)的易感基因，对1327例PBC患者和1120名健康对照进行了全基因组关联研究和随后的复制研究。两个显著的非人类白细胞抗原易感基因座(TNFSF15和POU2AF1)被鉴定出来。此外，在21个欧洲血统PBC的非HLA易感基因座中，有10个(CD80、IKZF3、IL7R、NFKB1、STAT4、CXCR5、TNFAIP2、MAP3K7IP1、rs6974491、DENND1B)与日本人群有显著关联。这些结果表明，T细胞(CD80、IL12A、IL12RB2、STAT4、TNFSF15)和B细胞(IL7R、CXCR5、POU2AF1、SPIB、IKZF3)的Th1/Th17分化在欧洲血统和日本人中都具有重要意义。此外，对TNFSF15编码的肿瘤坏死因子样配体1A(TL1A)的系统和局部表达的研究表明，TL1A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.