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Abstract
Juvenile rheumatoid arthritis (JRA) comprises a group of chronic systemic inflammatory disorders that primarily affect joints and can cause long-term disability. JRA is likely to be a complex genetic trait, or a series of such traits, with both genetic and environmental factors contributing to the risk for developing the disease and to its progression. The HLA region on the short arm of chromosome 6 has been intensively evaluated for genetic contributors to JRA, and multiple associations, and more recently linkage, has been detected. Other genes involved in innate and acquired immunity also map to near the HLA cluster on 6p, and it is possible that variation within these genes also confers risk for developing JRA. We examined the TPSN gene, which encodes tapasin, an endoplasmic reticulum chaperone that is involved in antigen processing, to elucidate its involvement, if any, in JRA. We employed both a case–control approach and the transmission disequilibrium test, and found linkage and association between the TPSN allele (Arg260) and the systemic onset subtype of JRA. Two independent JRA cohorts were used, one recruited from the Rheumatology Clinic at Cincinnati Children's Hospital Medical Center (82 simplex families) and one collected by the British Paediatric Rheumatology Group in London, England (74 simplex families). The transmission disequilibrium test for these cohorts combined was statistically significant (χ2 = 4.2, one degree of freedom; P = 0.04). Linkage disequilibrium testing between the HLA alleles that are known to be associated with systemic onset JRA did not reveal linkage disequilibrium with the Arg260 allele, either in the Cincinnati systemic onset JRA cohort or in 113 Caucasian healthy individuals. These results suggest that there is a weak association between systemic onset JRA and the TPSN polymorphism, possibly due to linkage disequilibrium with an as yet unknown susceptibility allele in the centromeric part of chromosome 6.
Highlights
Juvenile rheumatoid arthritis (JRA) is the most common chronic arthritic condition of childhood, encompassing pauciarticular, polyarticular, and systemic-onset disease subtypes
In the present study we report an association between the exon 4 tapasin gene (TPSN) polymorphism and susceptibility to systemic onset JRA (SoJRA), involving the TPSN allele Arg260 (01 allele)
The study cohort included 88 SoJRA affected families recruited in Cincinnati (US cohort) and 74 simplex SoJRA families identified by the British Paediatric Rheumatology Study Group (UK cohort)
Summary
Juvenile rheumatoid arthritis (JRA) is the most common chronic arthritic condition of childhood, encompassing pauciarticular, polyarticular, and systemic-onset disease subtypes. JRA is typically considered autoimmune in etiology, with characteristic T-cell abnormalities and chronic synovitis. JRA is probably a collection of diseases with complex overlapping etiologies, with each subtype influenced by multiple genetic susceptibility loci and mediated by environmental effects [1]. Genetic associations with MHC alleles have been documented primarily within the HLA class II region, and with certain class I alleles. These associations are df = degrees of freedom; IL = interleukin; JRA = juvenile rheumatoid arthritis; LD = linkage disequilibrium; MHC = major histocompatibility complex; PDT = pedigree disequilibrium test; SoJRA = systemic onset juvenile rheumatoid arthritis; TDT = transmission disequilibrium test; TNF = tumor necrosis factor
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