Raychaudhuri Soumya, Remmers Elaine F, Lee Annette T, Hackett Rachel, Guiducci Candace, Burtt Noël P, Gianniny Lauren, Korman Benjamin D, Padyukov Leonid, Kurreeman Fina A S, Chang Monica, Catanese Joseph J, Ding Bo, Wong Sandra, van der Helm-van Mil Annette H M, Neale Benjamin M, Coblyn Jonathan, Cui Jing, Tak Paul P, Wolbink Gert Jan, Crusius J Bart A, van der Horst-Bruinsma Irene E, Criswell Lindsey A, Amos Christopher I, Seldin Michael F, Kastner Daniel L, Ardlie Kristin G, Alfredsson Lars, Costenbader Karen H, Altshuler David, Huizinga Tom W J, Shadick Nancy A, Weinblatt Michael E, de Vries Niek, Worthington Jane, Seielstad Mark, Toes Rene E M, Karlson Elizabeth W, Begovich Ann B, Klareskog Lars, Gregersen Peter K, Daly Mark J, Plenge Robert M
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Nat Genet. 2008 Oct;40(10):1216-23. doi: 10.1038/ng.233. Epub 2008 Sep 14.
To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).
为了在欧洲人群中鉴定类风湿性关节炎风险基因座，我们对两项已发表的全基因组关联（GWA）研究进行了荟萃分析，这两项研究共计3393例病例和12462例对照。我们对31个先前未与类风湿性关节炎相关的排名靠前的单核苷酸多态性（SNP）进行了基因分型，这些SNP来自8个独立样本集合中的3929例自身抗体阳性类风湿性关节炎病例及5807例匹配对照的独立重复研究。我们在CD40基因座鉴定出一个常见变异（rs4810485，重复研究P = 0.0032，总体P = 8.2×10⁻⁹，比值比（OR） = 0.87）。连同TRAF1（参考文献2,3）和TNFAIP3（参考文献4,5）附近的其他关联，这表明CD40信号通路在类风湿性关节炎发病机制中起核心作用。我们还在CCL21基因座鉴定出关联（rs2812378，重复研究P = 0.00097，总体P = 2.8×10⁻⁷），该基因参与淋巴细胞运输。最后，我们在另外四个基因座鉴定出关联证据：MMEL1 - TNFRSF14（rs3890745，重复研究P = 0.0035，总体P = 1.1×10⁻⁷）、CDK6（rs42041，重复研究P = 0.010，总体P = 4.0×10⁻⁶）、PRKCQ（rs4750316，重复研究P = 0.0078，总体P = 4.4×10⁻⁶）以及KIF5A - PIP4K2C（rs1678542，重复研究P = 0.0026，总体P = 8.8×10⁻⁸）。
