CD40及其他基因座的常见变异会增加患类风湿性关节炎的风险。
Common variants at CD40 and other loci confer risk of rheumatoid arthritis.
作者信息
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
机构信息
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
出版信息
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）。
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