The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females. [Internal Medicine Journal]

Abstract

Aim: A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes. We sought to determine whether rs2476601 exhibits a female-specific association in JIA. Method(s): The discovery sample was drawn from the Australian CLARITY JIA biobank. Rs2476601 was genotyped in 413 cases (67% female, mean age at recruitment 9.1 years) and 690 healthy controls (42% female, mean age at recruitment 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype-bysex interaction analysis. We sought to replicate the sex-specific associations in an independent JIA case-control sample collected from the USA and Norway and held at the Children's Hospital of Philadelphia (1008 JIA cases and 9287 controls). Analyses were performed using Stata or PLINK. Result(s): PTPN22 rs2476601 was associated with JIA in both datasets (Discovery OR = 1.71,95% CI 1.26-2.33,p = 0.00066; Replication OR = 1.30, 95% CI 1.09-1.55, p = 0.0068). The association remained when adjusted for sex (Discovery OR = 1.63, 95% CI 1.18-2.24, p = 0.0028; Replication OR = 1.30, 95% CI 1.08-1.56, p = 0.0051). Discovery sample sex stratified analyses demonstrated association in females (OR = 2.35, 95% 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 also observed in the replication sample (Female OR = 1.38, 95% CI 1.09-1.73, p = 0.0068; MaleOR = 1.19,95% CI 0.88-1.63, p = 0.26). There was evidence for genotype-by-sex interaction (p interaction = 0.0087). Conclusion(s): We have demonstrated that the association between PTPN22 rs2476601 and JIA appears restricted to females, helping to explain the greater number of females that develop this disease.