Objective 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.
Methods 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.
Results The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (pFDRcorrected=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 (pFDRcorrected=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 (pFDRcorrected=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).
Conclusion 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.
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Funding This work was supported by grants SAF2009-11110, Junta de Andalucía, grants CTS-4977 and CTS-180 and by the RETICS Program, RD08/0075 (RIER) from the Instituto de Salud Carlos III (ISCIII). BR was supported by the I3P CSIC programme funded by the ‘Fondo Social Europeo’. LMDG was supported by COLFUTURO and the ‘Ayudas Predoctorales de Formación en Investigación en Salud (PFIS – FI09/00544)’ from the Instituto de Salud Carlos III. The USA contributors were supported by NIH/NIAMS grants P50AR054144, N01-AR-0-2251 and NIH/NCRR 3UL1RR024148.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of each ethics committee of the participating hospitals.
Provenance and peer review Not commissioned; externally peer reviewed
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