Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan. [corrected]
Ann Rheum Dis. 2011 Mar;70(3):454-62. doi: 10.1136/ard.2010.130138. Epub 2010 Dec 3.
Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.
3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc.
The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1).
The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.
PTPN22 基因中的两个功能性单核苷酸多态性（SNP）（rs24746601 和 rs33996649）与自身免疫有关。本研究的目的是首次研究 R263Q SNP 的作用，并重新评估 R620W SNP 在系统性硬化症（SSc）易感性和临床表型中的作用。
我们纳入了来自西班牙初始病例对照研究和另外七个独立验证队列的 3422 例 SSc 患者（2020 例局限性皮肤 SSc 和 1208 例弥漫性皮肤 SSc）和 3638 例高加索裔健康对照者。采用 TaqMan 等位基因鉴别检测法对 rs33996649 和 rs2476601 PTPN22 多态性进行基因分型。进行荟萃分析以检验这些 PTPN22 多态性在 SSc 中的总体作用。
荟萃分析显示 rs2476601 T 等位基因与 SSc 易感性相关（校正 FDR 值后 p=0.03，合并 OR 1.15，95%CI 1.03 至 1.28）。此外，rs2476601 T 等位基因与抗着丝点阳性状态显著相关（校正 FDR 值后 p=0.02，合并 OR 1.22，95%CI 1.05 至 1.42）。尽管西班牙人群中 rs33996649 A 等位基因与 SSc 显著相关（校正 FDR 值后 p=0.04，OR 0.58，95%CI 0.36 至 0.92），但荟萃分析并未证实这种相关性（合并 p=0.36，OR 0.89，95%CI 0.72 至 1.1）。
本研究提示 PTPN22 R620W 多态性影响 SSc 遗传易感性，但新的 R263Q 遗传变异没有影响。这些数据进一步证实了 R620W 突变是自身免疫性疾病的常见危险因素。
