Han Tae-Un, Bang So-Young, Kang Changwon, Bae Sang-Cheol
Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Arthritis Rheum. 2009 Sep;60(9):2577-84. doi: 10.1002/art.24759.
Recent genome-wide association scans and replication studies of European populations have disclosed several single-nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA) susceptibility. The aim of this study was to evaluate the RA-associated loci by genotyping previously reported SNPs and additional tag SNPs in a Korean population.
A total of 1,316 unrelated RA patients and 1,006 controls were genotyped for 12 SNPs identified in genome-wide scans and for 12 additional tag SNPs in IL2RB, OLIG3-TNFAIP3, PTPN22, and TRAF1-C5, and the findings were statistically compared.
None of the SNPs tested was associated with RA susceptibility, except rs7021206 in TRAF1 intron 3 (P = 0.0032) and, among the SNPs previously reported, rs6457617 in HLA (P = 4.6 x 10(-35)). The association of rs7021206 was positive in patients who were seropositive for rheumatoid factor (P = 0.0051) or for anti-cyclic citrullinated peptide autoantibodies (P = 0.0062). However, Korean patients were negative for the association of rs3761847 in the TRAF1-C5 intergenic region previously reported in Caucasians. Linkage disequilibrium between rs3761847 and rs7021206 was not as high in Koreans (r(2) = 0.37) as in Caucasians (r(2) = 0.67), which explains the lack of association of rs3761847 in Koreans. Accordingly, RA susceptibility was localized to an extended haplotype marked by rs7021206 rather than rs3761847, and SNPs highly correlated with rs7021206 (r(2) > or = 0.81) extended from rs1953126 in the PHF19-TRAF1 intergenic region to rs2900180 in the TRAF1-C5 intergenic region, spanning 66 kb.
Our results demonstrate that within and around TRAF1, excluding PHF19 and C5, SNPs highly correlated with rs7021206, but not those correlated with rs3761847, are associated with RA in both Asians and Caucasians and are possibly correlated with causative variations.
近期针对欧洲人群的全基因组关联扫描及重复研究已发现了多个与类风湿关节炎（RA）易感性相关的单核苷酸多态性（SNP）。本研究旨在通过对韩国人群中先前报道的SNP及额外的标签SNP进行基因分型，来评估与RA相关的基因座。
对1316例无亲缘关系的RA患者和1006例对照进行基因分型，检测在全基因组扫描中鉴定出的12个SNP以及在IL2RB、OLIG3 - TNFAIP3、PTPN22和TRAF1 - C5中的12个额外标签SNP，并对结果进行统计学比较。
除TRAF1内含子3中的rs7021206（P = 0.0032）以及先前报道的SNP中HLA的rs6457617（P = 4.6×10⁻³⁵）外，所检测的SNP均与RA易感性无关。rs7021206在类风湿因子血清学阳性（P = 0.0051）或抗环瓜氨酸肽自身抗体血清学阳性（P = 0.0062）的患者中呈阳性关联。然而，韩国患者对于先前在白种人中报道的TRAF1 - C5基因间区域的rs3761847的关联呈阴性。rs3761847与rs7021206之间的连锁不平衡在韩国人中（r² = 0.37）不如在白种人中（r² = 0.67）高，这解释了rs3761847在韩国人中缺乏关联的原因。因此，RA易感性定位于以rs7021206而非rs3761847为标记的扩展单倍型，并且与rs7021206高度相关（r²≥0.81）的SNP从PHF19 - TRAF1基因间区域的rs1953126延伸至TRAF1 - C5基因间区域的rs2900180，跨度为66 kb。
我们的结果表明，在TRAF1内部及周围，排除PHF19和C5，与rs7021206高度相关而非与rs3761847相关的SNP在亚洲人和白种人中均与RA相关，并且可能与致病变异相关。
