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

Authors

  • Rebecca Lamb,

    Corresponding author
    1. University of Manchester, Manchester, UK
    • Arthritis Research Campaign Epidemiology Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
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  • Wendy Thomson,

    1. University of Manchester, Manchester, UK
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  • Emma Ogilvie,

    1. University College London, London, UK
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  • the British Society of Paediatric and Adolescent Rheumatology,

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    • Contributors to The British Society of Paediatric and Adolescent Rheumatology are Dr. M. Abinun, Dr. M. Becker, Dr. A. Bell, Professor A. Craft, Dr. E. Crawley, Dr. J. David, Dr. H. Foster, Dr. J. Gardener-Medwin, Dr. J. Griffin, Dr. A. Hall, Dr. M. Hall, Dr. A. Herrick, Dr. P. Hollingworth, Dr. L. Holt, Dr. S. Jones, Dr. G. Pountain, Dr. C. Ryder, Professor T. Southwood, Dr. I. Stewart, Dr. H. Venning, L. Wedderburn, Professor P. Woo, and Dr. S. Wyatt.

  • Rachelle Donn

    1. University of Manchester, Manchester, UK
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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.

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