Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis

Abstract

Objective: Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors.

Methods: Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results: The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA.

Conclusion: We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.

Figure 1. Case-control association results of STAT4 variant rs7574865

RA: rheumatoid arthritis, SLE: systemic lupus erythematosus, T1D: type 1 diabetes, SS: Sjogren’s syndrome, IBD: inflammatory bowel disease, MS: Multiple sclerosis. OR: Odds ratio (Allelic). OR (Vertical line) and 95% confidence intervals (horizontal lines) are shown. Red color indicates pooled analyses of RA and SLE studies. Blue color indicates JIA association.