Genome-Wide Association Study of Rheumatoid Arthritis in Koreans
Genome-Wide Association Study of Rheumatoid Arthritis in Koreans
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DOI：
10.1002/art.30235
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发表时间：
2011-04-01
影响因子：
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通讯作者：
Bae, Sang-Cheol
中科院分区：
文献类型：
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作者：
Freudenberg, Jan;Lee, Hye-Soon;Bae, Sang-Cheol
目标。在韩国人中进行全基因组关联研究（GWAS），以确定类风湿关节炎（RA）的易感位点。我们在801例RA病例和757例对照中获得了441,398个单核苷酸多态性（snp）的高质量基因型。然后，我们对来自46个基因座的79个标记在718例RA病例和719例对照的独立样本中进行了复制测试。来自主要组织相容性复合体区域和PADI4基因的标记获得全基因组显著性（P < 5 × 10(-08)）。复制数据显示，46个复制位点中有11个位点的标记存在显著的关联信号（P < 5 × 10(-02)），大大超出随机预期。在复制阶段和综合分析中最重要的基因包括已知的欧洲RA位点BLK、AFF3和CCL21。因此，除了先前相关的STAT4等位基因外，这三个位点的变异可能不仅在欧洲人之间，而且在亚洲人中也可能导致RA。此外，我们在PTPN2、FLI1、ARHGEF3、LCP2、GPR137B、TRHDE和CGA1基因附近观察到复制信号。根据复制阶段研究中过量的小P值，我们估计这些位点中有一半以上是真正的RA易感基因。最后，我们系统地分析了韩国人在已建立的欧洲RA位点上存在的关联信号，结果表明韩国人的RA位点中欧洲RA位点显著富集。在亚洲和欧洲人群的比较中，RA的遗传风险既涉及人群特异性位点，也涉及许多共同的遗传易感位点。
Objective. To perform a genome-wide association study (GWAS) in Koreans in order to identify susceptibility loci for rheumatoid arthritis (RA).Methods. We generated high-quality genotypes for 441,398 single-nucleotide polymorphisms (SNPs) in 801 RA cases and 757 controls. We then tested 79 markers from 46 loci for replication in an independent sample of 718 RA cases and 719 controls.Results. Genome-wide significance (P < 5 x 10(-08)) was attained by markers from the major histocompatibility complex region and from the PADI4 gene. The replication data showed nominal association signals (P < 5 x 10(-02)) for markers from 11 of the 46 replicated loci, greatly exceeding random expectation. Genes that were most significant in the replication stage and in the combined analysis include the known European RA loci BLK, AFF3, and CCL21. Thus, in addition to the previously associated STAT4 alleles, variants at these three loci may contribute to RA not only among Europeans, but also among Asians. In addition, we observed replication signals near the genes PTPN2, FLI1, ARHGEF3, LCP2, GPR137B, TRHDE, and CGA1. Based on the excess of small P values in the replication stage study, we estimate that more than half of these loci are genuine RA susceptibility genes. Finally, we systematically analyzed the presence of association signals in Koreans at established European RA loci, which showed a significant enrichment of European RA loci among the Korean RA loci.Conclusion. Genetic risk for RA involves both population-specific loci as well as many shared genetic susceptibility loci in comparisons of Asian and European populations.