Wnt‐1–inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis

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Abstract
Objective To determine whether Wnt‐1–inducible signaling pathway protein 3 (WISP3) polymorphisms are associated with susceptibility to juvenile idiopathic arthritis (JIA). Methods The exons and the intron/exon boundaries of the WISP3 gene were mutation‐screened by denaturing high‐performance liquid chromatography in 86 patients with polyarticular‐course JIA (≥5 joints affected) and 15 controls. Seven single‐nucleotide polymorphisms (SNPs) were genotyped, using allelic discrimination, in a case–control study. Initially, 159 patients with polyarticular‐course JIA and 263 controls were studied, followed by study of a replication cohort of 181 patients with polyarticular‐course JIA and 355 controls. Available parents of patients with polyarticular‐course JIA were also genotyped. Finally, other JIA subgroups were studied (initial cohort, n = 218; replication cohort, n = 213). Single‐point and haplotype analysis was carried out. Results Positive association with SNP WISP3*G84A was observed and replicated in 2 cohorts of patients with polyarticular‐course JIA. Specifically, homozygosity of the mutant allele (WISP3*84AA) conferred a 2‐fold increased risk of disease susceptibility (for the initial cohort, odds ratio [OR] 2.1, 95% confidence interval [95% CI] 1.1–4.2, P = 0.03; for the replication cohort, OR 2.0, 95% CI 1.0–4.3, P = 0.05). Strong linkage disequilibrium was observed between SNPs; however, no haplotypic effect of an order of magnitude greater than the single‐point WISP3*G84A association was observed. Using the transmission disequilibrium test, a trend toward overtransmission of the WISP3*84A allele was observed in patients with polyarticular‐course JIA. No association of any WISP3 polymorphism was observed in the other JIA subgroups. Conclusion Association and replication of a polymorphism within the first intron of the WISP3 gene have been shown in patients with polyarticular‐course JIA. The functional significance of the WISP3*G84A SNP is being determined.