Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis.
Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis.
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DOI：
10.1038/srep27563
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发表时间：
2016-06-08
影响因子：
4.6
通讯作者：
Bae SC
中科院分区：
文献类型：
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作者：
Kim K;Bang SY;Ikari K;Yoo DH;Cho SK;Choi CB;Sung YK;Kim TH;Jun JB;Kang YM;Suh CH;Shim SC;Lee SS;Lee J;Chung WT;Kim SK;Choe JY;Momohara S;Taniguchi A;Yamanaka H;Nath SK;Lee HS;Bae SC
在自身免疫性疾病（例如，类风湿性关节炎），但也有一些特殊的基因座显示群体间的异源关联。在这里，我们调查了亚洲和欧洲人群中对类风湿性关节炎发展具有不同影响的遗传变异。使用Cochran同质性检验，对来自大型亚洲（n = 14，465; 9，299名发现受试者和5，166名验证受试者; 4个收集）和欧洲（n = 45，790; 11个收集）类风湿性关节炎病例对照队列的疾病相关数据进行了检查，并使用免疫芯片和全基因组SNP阵列数据。我们确定了两个祖先之间GTF 2 I基因座常见变异的显著异质性（在rs73366469处P异质性= 9.6 × 10−9），并表明这种异质性是由于亚洲特异性关联效应（亚洲人的ORMeta = 1.37和PMeta = 4.2 × 10−13;欧洲人的ORMeta = 1.00和PMeta = 1.00）。跨祖先的比较和生物信息学分析揭示了一个可能的因果或疾病变异标记SNP（rs 117026326;与rs73366469连锁不平衡），其次要等位基因在亚洲人中很常见，但在欧洲人中很少见。总之，我们通过异质性定位和复制研究，在GTF 2 I的人类非HLA区域中确定了对亚洲类风湿性关节炎有史以来最大的影响，并确定了一个可能的因果变异。
Considerable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran’s homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (PHeterogeneity = 9.6 × 10−9 at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and PMeta = 4.2 × 10−13 in Asians; ORMeta = 1.00 and PMeta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.