Orozco Gisela, Hinks Anne, Eyre Steve, Ke Xiayi, Gibbons Laura J, Bowes John, Flynn Edward, Martin Paul, Wilson Anthony G, Bax Deborah E, Morgan Ann W, Emery Paul, Steer Sophia, Hocking Lynne, Reid David M, Wordsworth Paul, Harrison Pille, Thomson Wendy, Barton Anne, Worthington Jane
arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester M13 9PT, UK.
Hum Mol Genet. 2009 Jul 15;18(14):2693-9. doi: 10.1093/hmg/ddp193. Epub 2009 May 5.
The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 x 10(-6), OR (95% CI) 1.22 (1.13-1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95% CI) 0.86 (0.8-0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95% CI) (1.51-2.29)]. This equates to an effect size of 1.50 (95% CI 1.21-1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.
风湿性关节炎（RA）全基因组关联研究（GWAS）中最一致的发现是与6号染色体长臂23区（6q23）的一个单核苷酸多态性（SNP）相关。我们对该区域进行了精细定位，以便在6q23区域寻找其他疾病变异。该研究纳入了3962例RA患者和3531例健康对照。我们发现了18个与RA相关的SNP。关联最强的SNP是rs6920220 [P = 2.6×10⁻⁶，比值比（95%可信区间）1.22（1.13 - 1.33）]。其次关联最强的SNP是rs13207033 [P = 0.0001，比值比（95%可信区间）0.86（0.8 - 0.93）]，它与rs10499194完全相关，rs10499194是先前在美国/欧洲研究系列中与RA相关的一个SNP。此外，我们还发现了一些新的潜在RA标志物，包括位于TNFAIP3基因内含子2中的rs5029937。在这18个相关SNP中，经过条件逻辑回归分析后，rs6920220、rs13207033和rs5029937这三个多态性仍然显著。与无风险等位基因携带者相比，rs6920220和rs5029937的风险等位基因携带者与rs13207033的保护性等位基因缺失的组合与RA强烈相关[比值比为1.86（95%可信区间）（1.51 - 2.29）]。与对照组相比，这相当于效应大小为1.50（95%可信区间1.21 - 1.85），且高于任何单个SNP所获得的效应大小。这是第一项表明，一旦考虑到其他风险变异的影响，全基因组关联研究中已确认的位点，尽管其效应大小适度，但可能蕴藏着显著更大的效应的研究。
