Wnt-1-inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis.
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.


CONCLUSIONS
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.
Lamb
Rebecca
R
Arthritis Research Campaign Epidemiology Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. rebecca.lamb@man.ac.uk
Thomson
Wendy
W
Ogilvie
Emma
E
Donn
Rachelle
R
D001171:Arthritis, Juvenile / Q000097:blood / Q000235:genetics* / Q000473:pathology; D055511:CCN Intercellular Signaling Proteins; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006720:Homozygote; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood / Q000235:genetics*; D007438:Introns; D008297:Male; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics*; D010290:Parents; D020641:Polymorphism, Single Nucleotide
D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins