Association of IL12A Expression Quantitative Trait Loci (eQTL) With Primary Biliary Cirrhosis in a Chinese Han Population.
Association of IL12A Expression Quantitative Trait Loci (eQTL) With Primary Biliary Cirrhosis in a Chinese Han Population.
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IL12A表达数量性状位点（eQTL）与中国汉族人群原发性胆汁性肝硬化的关联
DOI：
10.1097/md.0000000000003665
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发表时间：
2016-05
期刊：
影响因子：
1.6
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Li P;Lu G;Cui Y;Wu Z;Chen S;Li J;Wen X;Zhang H;Mu S;Zhang F;Li Y
摘要欧洲个体的全基因组关联研究表明，IL12A 与原发性胆汁性肝硬化 (PBC) 密切相关。然而，在中国汉族和日本人群中进行的重复研究中并未检测到这种关联。 为了验证 IL12A 遗传变异对中国人群 PBC 发病机制的贡献，在 586 例 PBC 病例和 726 名健康对照人群中对 IL12A 基因位点周围 22 个单核苷酸多态性 (SNP) 进行了重复研究。 22 个 SNP 中的 3 个与 PBC 显着相关。关联信号最显着的 2 个 SNP 是 rs4679868 (P = 6.59E−05，比值比 [OR] = 1.554 [1.253–1.927]) 和 rs6441286 (P = 8.00E−05，OR = 1.551) [1.250–1.924]）。这 2 个 SNP 彼此之间存在很强的连锁性 (r2 = 0.981)，并且均被发现与欧洲人群中的 PBC 显着相关。基于这 2 个 SNP 位于 HEK293 细胞系中经荧光素酶报告系统验证的 2 个增强子附近的观察结果，进行了表达数量性状位点 (eQTL) 分析。使用公开数据进行的 eQTL 分析结果显示，rs4679868 和 rs6441286 的风险等位基因与源自中国汉族个体的淋巴母细胞系中 IL12A 表达降低显着相关（rs4679868 的 P = 0.0031，rs4679868 的 P = 0.0073） rs6441286）。此外，这2个SNP的风险等位基因与IL12A上游91.5 kb的乳糜泻易感基因SCHIP1的下调显着相关。这些结果不仅证明IL12A与中国汉族人群的PBC相关，而且还确定了其参与PBC发病的潜在机制。
AbstractGenome-wide association studies in European individuals have revealed that IL12A is strongly associated with primary biliary cirrhosis (PBC). However, this association was not detected in replicative studies conducted in Chinese Han and Japanese populations.To verify contributions of genetic variants of IL12A to the pathogenesis of PBC in Chinese populations, a replicative study of 22 single nucleotide polymorphisms (SNPs) around the IL12A gene locus was performed in a cohort of 586 PBC cases and 726 healthy controls. Three out of the 22 SNPs were significantly associated with PBC. The 2 SNPs with the most significant association signal were rs4679868 (P = 6.59E−05, odds ratio [OR] = 1.554 [1.253–1.927]) and rs6441286 (P = 8.00E−05, OR = 1.551 [1.250–1.924]). These 2 SNPs were strongly linked to each other (r2 = 0.981), and both were found to be significantly associated with PBC in European populations.An expression quantitative trait loci (eQTL) analysis was performed based on the observation that these 2 SNPs were located in proximity to 2 enhancers verified by luciferase reporter systems in the HEK293 cell line. The results of eQTL analysis, conducted using the publically accessible data, showed that the risk alleles of rs4679868 and rs6441286 were significantly associated with decreased expression of IL12A in lymphoblastoid cell lines derived from individuals of Chinese Han ancestry (P = 0.0031 for rs4679868 and P = 0.0073 for rs6441286). In addition, the risk alleles of the 2 SNPs were significantly associated with down-regulation of SCHIP1, a celiac disease susceptible gene, 91.5 kb upstream of IL12A.These results not only demonstrated that IL12A is associated with PBC in the Chinese Han population but also identified a potential mechanism for its involvement in the pathogenesis of PBC.