Background/Purpose: Over the last few years, there have been numerous reports of associations of single nucleotide polymorphisms (SNPs) at various genetic loci with juvenile idiopathic arthritis (JIA). However, apart from a select few variants, the majority of these association findings would benefit from further replication in independent populations to confirm their involvement in disease risk. We examined a total of 60 SNPs in or around 44 genes previously examined by others for association with (total) JIA in the ChiLdhood Arthritis Risk factor Identification sTudY (CLARITY), a new Australian collection of cases and healthy child controls.

Methods: DNA from a total of 324 JIA cases (mean age 9.7 years, 67.3% female) and 568 controls (mean age 7.8 years, 40.7% female) was available for genotyping. Genes and SNPs were chosen based on reports by others over the last five years, and included PTPN22 (rs 2476601), IL2RA (rs706778), ATXN2 (rs653178), C12orf30 (rs17696736), C3orf1 (rs4688011), JMJDC1 (rs12411988), PTPN2 (rs7234029), STAT4 (rs7574865), TRAF1/C5 (rs2900180), and VTCN1(rs12046117). SNPs were genotyped using the Sequenom MassARRAY system. Allelic and genotypic association analyses were performed using PLINK. A p < 0.05, along with an odds ratio (OR) in the same direction as the original association report(s) was taken as evidence of replication of the prior findings.

Results: Following data QC, 292 cases and 497 controls were analysed. Evidence of replication was generated for PTPN22 (Allelic OR = 1.67; 95% CI 1.16, 2.40; p (best test) = 0.006), ATXN2 (OR = 1.54; 95% CI 1.25, 1.89; p = 3.8×10^-5), C12orf30 (OR = 1.47; 95% CI 1.20, 1.81, p = 0.0002), C3orf1 (OR = 1.32; 95% CI 1.03, 1.69; p = 0.030), STAT4 (OR = 1.38; 95% CI 1.10, 1.74; p = 0.003), and TRAF1/C5 (OR = 1.24; 95% CI 1.00, 1.53; p = 0.021). We were unable to confirm association with IL2RA, PTPN2, and VTCN1; however, this may reflect a lack of statistical power since ORs were directionally consistent with previous reports. Results for JMJDC1were neither statistically significant, nor were the ORs directionally consistent. Restriction of the dataset to 204 cases and 248 controls in whom Caucasian ancestry of all four grandparents could be confirmed did not materially alter these findings.

Conclusion: We have provided further confirmation of association of (total) JIA with a number of genes, adding to the growing international data that is clarifying the underlying genetic risk component of this serious childhood disease. Pooling of currently available candidate gene data for meta-analyses, and pooling of samples for large genome-wide association study efforts will likely provide further clarity. Future work to better define the overall JIA risk profile should also include an examination of gene-gene and gene-environment interactions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/replication-analysis-of-non-hla-gene-variants-with-prior-evidence-of-association-with-juvenile-idiopathic-arthritis/