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

Abstract

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 (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.

Association of juvenile idiopathic arthritis with PTPN22 rs2476601 is specific to females in a Greek population

“…Exclusion of systemic JIA cases did not materially alter the findings. This sex-specific pattern of association, including the direction of effect, is consistent with the prior study conducted in Australian, US and Norwegian samples [ 16 ]. Given that the sex bias differs by JIA subtype, ideally we would have liked to test for these associations in individual subtypes; however, small sample size (for details see [ 6 ]) prevented us from performing these analyses with any statistical certainty.…”

“…In relation to JIA, it was recently reported that PTPN22 rs2476601 is associated with JIA only in females in an Australian case-control sample. The finding was replicated in a second case-control sample from the US and Norway [ 16 ]. This present study aimed to investigate whether the female-specific association can also be observed in further ethnic groups by performing sex stratified association analysis in a Greek JIA case-control sample.…”

“…For analyses where logistic regression could not be performed because of the absence of the minor allele in any one group, we used the Gart method [ 17 ] with a continuity correction delta = 0.5 (also known as the Woolf method) to estimate ORs and 95 % CIs, and Fisher’s exact test to determine the P -value. We also performed a ‘pooled control’ analysis (female cases compared to all controls and male cases combined), following past work on PTPN22 and JIA in other populations [ 16 ]. A P value less than 0.05 was considered significant.…”

Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan

“…The polymorphism rs2476601 has been found to be significantly associated with juvenile RA in female but not in male patients, with evidence of a genotype-by-sex interaction (165). Early menarche at age <12 years was inversely associated with RA (166, 167) and found to be protective factor in one study (168).…”

The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism and Susceptibility to Autoimmune Diseases

“…Several reports indicate that PTPN22 C1858T polymorphism has been consistently associated with JIA ( Table 5). PTPN22 C1858T polymorphism is associated with JIA in Australians [70,71], Americans of European ancestry [67], Czech [72], Europeans [69], Greek [73], Norwegians [74], UK population [65], and Egyptians [75]. Two separate meta-analyses also indicated that PTPN22 C1858T is associated with susceptibility to JIA [76,77].…”