The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P =0.00011) but not males (OR=0.91, 95% CI=0.52–1.60, P =0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction ( P interaction =0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.