Freudenberg Jan, Lee Hye-Soon, Han Bok-Ghee, Shin Hyoung Do, Kang Young Mo, Sung Yoon-Kyoung, Shim Seung-Cheol, Choi Chan-Bum, Lee Annette T, Gregersen Peter K, Bae Sang-Cheol
Feinstein Institute for Medical Research and North Shore-Long Island Jewish Health System, Manhasset, New York, NY, USA.
Arthritis Rheum. 2011 Apr;63(4):884-93. doi: 10.1002/art.30235.
To perform a genome-wide association study (GWAS) in Koreans in order to identify susceptibility loci for rheumatoid arthritis (RA).
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.
Genome-wide significance (P < 5 × 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 × 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.
Genetic risk for RA involves both population-specific loci as well as many shared genetic susceptibility loci in comparisons of Asian and European populations.
在韩国人群中开展全基因组关联研究（GWAS），以确定类风湿关节炎（RA）的易感基因座。
我们对801例RA患者和757例对照的441,398个单核苷酸多态性（SNP）生成了高质量的基因型。然后，我们在718例RA患者和719例对照的独立样本中对来自46个基因座的79个标记进行了复制测试。
主要组织相容性复合体区域和PADI4基因的标记达到了全基因组显著性水平（P < 5 × 10⁻⁸）。复制数据显示，46个复制基因座中的11个标记存在名义关联信号（P < 5 × 10⁻²），大大超过了随机预期。在复制阶段和联合分析中最显著的基因包括已知的欧洲RA基因座BLK、AFF3和CCL21。因此，除了先前关联的STAT4等位基因外，这三个基因座的变异不仅可能在欧洲人中，也可能在亚洲人中导致RA。此外，我们在PTPN2、FLI1、ARHGEF3、LCP2、GPR137B、TRHDE和CGA1基因附近观察到了复制信号。基于复制阶段研究中出现的大量小P值，我们估计这些基因座中超过一半是真正的RA易感基因。最后，我们系统分析了韩国人在已确定的欧洲RA基因座处的关联信号，结果显示韩国RA基因座中欧洲RA基因座显著富集。
在亚洲和欧洲人群的比较中，RA的遗传风险涉及特定人群的基因座以及许多共同的遗传易感基因座。
