Serrano A, Márquez A, Mackie SL, Carmona FD, Solans R, Miranda-Filloy JA, Hernández-Rodríguez J, Cid MC, Castañeda S, Morado IC, Narváez J, Blanco R, Sopeña B, García-Villanueva MJ, Monfort J, Ortego-Centeno N, Unzurrunzaga A, Marí-Alfonso B, Sánchez Martín J, de Miguel E, Magro C, Raya E, Braun N, Latus J, Molberg O, Lie BA, Moosig F, Witte T, Morgan AW, González-Gay MA, and Martín J
Objective: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA)., Methods: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays., Results: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79)., Conclusions: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.