Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden:: Association of susceptibility with PTPN22, CTLA4, and PADI4
Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden:: Association of susceptibility with PTPN22, CTLA4, and PADI4
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DOI：
10.1086/498651
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发表时间：
2005-12-01
影响因子：
9.8
通讯作者：
Rioux, JD
中科院分区：
文献类型：
--
作者：
Plenge, RM;Padyukov, L;Rioux, JD
类风湿性关节炎（RA）中的代谢物-基因关联研究已经导致了令人鼓舞但明显不一致的结果。不一致的一种解释是，在真实效应的先验概率较低的情况下，检测适度效应的功效不足。为了克服这一局限性，我们选择了等位基因的疾病关联的概率增加的基础上，对RA和其他自身免疫性疾病的文献综述，并测试它们与RA易感性的样本收集功率检测适度的遗传效应。我们检测了来自北美风湿性关节炎协会（NARAC）和瑞典风湿性关节炎流行病学调查（EIRA）收集的2，370例RA病例和1，757例对照的14个基因的17个等位基因。我们发现了PTPN 22与抗瓜氨酸抗体阳性RA发生相关的强有力证据（优势比[OR] 1.49; P = .001），使用了以前未检测的EIRA样本。我们支持CTLA 4（CT60等位基因，OR 1.23; P = 0.001）和PADI 4（PADI 4_94，OR 1.24; P = 0.001）与RA的发生相关，但仅在NARAC队列中。在两个队列中抗瓜氨酸抗体血清阳性的RA患者中，CTLA 4的相关性更强（P = .006）。我们的数据集与临床相关的RA子集的探索显示，PTPN 22与疾病发作的年龄较早相关（P = .004），PTPN 22在男性中的作用强于女性（P = .03）。一项荟萃分析未能证明其余等位基因与RA易感性的相关性，这表明先前发表的相关性可能代表假阳性结果。鉴于本研究中复制真阳性关联的强大统计能力，我们的结果为PTPN 22，CTLA 4和PADI 4作为RA易感基因提供了支持，并证明了与RA临床相关子集的新关联。
Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody positive RA (odds ratio [OR] 1.49; P = .001), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P = .001) and PADI4 (PADI4_94, OR 1.24; P = .001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P = .006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P = .004) and that PTPN22 has a stronger effect in males than in females (P = .03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.