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Tapasin Gene Polymorphism in Systemic Onset Juvenile Rheumatoid Arthritis

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Tapasin Gene Polymorphism in Systemic Onset Juvenile Rheumatoid Arthritis Available online http://arthritis-research.com/content/7/2/R285 ResearchVol 7 No 2 article Open Access Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case–control study Hulya Bukulmez1,2,3,4, Mark Fife5, Monica Tsoras1, Susan D Thompson1, Natalie A Twine5, Patricia Woo5, Jane M Olson2, Robert C Elston2, David N Glass1 and Robert A Colbert1 1William S. Rowe Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA 2Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA 3Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA 4Pediatric Rheumatology, Pediatrics, Metro Health Medical Center, Case Western Reserve University, Cleveland, Ohio, USA 5The Center for Pediatric and Adolescent Rheumatology, University College London, London, UK Corresponding author: Hulya Bukulmez, [email protected] Received: 13 Mar 2004 Revisions requested: 13 May 2004 Revisions received: 17 Nov 2004 Accepted: 22 Nov 2004 Published: 11 Jan 2005 Arthritis Res Ther 2005, 7:R285-R290 (DOI 10.1186/ar1480)http://arthritis-research.com/content/7/2/R285 © 2005 Bukulmez et al., licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/ 2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is cited. Abstract Juvenile rheumatoid arthritis (JRA) comprises a group of chronic the systemic onset subtype of JRA. Two independent JRA systemic inflammatory disorders that primarily affect joints and cohorts were used, one recruited from the Rheumatology Clinic can cause long-term disability. JRA is likely to be a complex at Cincinnati Children's Hospital Medical Center (82 simplex genetic trait, or a series of such traits, with both genetic and families) and one collected by the British Paediatric environmental factors contributing to the risk for developing the Rheumatology Group in London, England (74 simplex families). disease and to its progression. The HLA region on the short arm The transmission disequilibrium test for these cohorts combined of chromosome 6 has been intensively evaluated for genetic was statistically significant (χ2 = 4.2, one degree of freedom; P contributors to JRA, and multiple associations, and more = 0.04). Linkage disequilibrium testing between the HLA alleles recently linkage, has been detected. Other genes involved in that are known to be associated with systemic onset JRA did not innate and acquired immunity also map to near the HLA cluster reveal linkage disequilibrium with the Arg260 allele, either in the on 6p, and it is possible that variation within these genes also Cincinnati systemic onset JRA cohort or in 113 Caucasian confers risk for developing JRA. We examined the TPSN gene, healthy individuals. These results suggest that there is a weak which encodes tapasin, an endoplasmic reticulum chaperone association between systemic onset JRA and the TPSN that is involved in antigen processing, to elucidate its polymorphism, possibly due to linkage disequilibrium with an as involvement, if any, in JRA. We employed both a case–control yet unknown susceptibility allele in the centromeric part of approach and the transmission disequilibrium test, and found chromosome 6. linkage and association between the TPSN allele (Arg260) and Keywords: association, linkage, juvenile rheumatoid arthritis, tapasin, TPSN, transmission disequilibrium testing Introduction est morbidity. JRA is probably a collection of diseases with Juvenile rheumatoid arthritis (JRA) is the most common complex overlapping etiologies, with each subtype influ- chronic arthritic condition of childhood, encompassing enced by multiple genetic susceptibility loci and mediated pauciarticular, polyarticular, and systemic-onset disease by environmental effects [1]. The MHC on the short arm of subtypes. JRA is typically considered autoimmune in etiol- chromosome 6 has been intensively analyzed, and associ- ogy, with characteristic T-cell abnormalities and chronic ations with both HLA and non-HLA genes have been synovitis. The extent of synovitis may range from minimal to reported. Genetic associations with MHC alleles have severe, and vary in terms of number of joints involved, with been documented primarily within the HLA class II region, systemic onset disease typically associated with the great- but also 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 necro- sis factor. R285 Arthritis Research & Therapy Vol 7 No 2 Bukulmez et al. largely JRA subtype and age specific [2], and are strongest CTG GGT AAG GGA CA-3'). HLA types were determined for pauciarticular and polyarticular disease [1]. For sys- for a subgroup of the participants using DNA-based low- temic onset JRA (SoJRA), associations with HLA-B8, HLA- resolution methodology (Geno-Vision Inc., Exton, PA, Bw35 [3,4] and HLA-DR4 [3,5] have been observed, USA), and serologically using standard typing sera and whereas HLA-DPB1*0401 was reported to have a protec- microcytotoxicity assays. tive effect in one Caucasian population [6]. Associations with HLA-DRB1*0401 and HLA-DRB1*0405 have been Preliminary association analysis was conducted by χ2 test- reported in a Japanese population [7]. Most of these asso- ing on contingency tables comparing the three genotypic ciations have not been replicated. frequencies between cases and control individuals to yield a χ2 with two degrees of freedom. Family-based associa- In the present study we targeted the tapasin gene (TPSN), tion analysis was performed using the transmission disequi- which is in the class II region of the MHC, 180 kilobases librium test (TDT). The TDT [13,14] is a family-based centromeric of HLA-DP. The tapasin protein is necessary association test that compares within a cohort the number for the proper assembly and peptide-presenting function of of times a particular parental allele is transmitted to an HLA class I molecules [8]. The TPSN gene has a polymor- affected offspring versus the number of times it is not trans- phism in exon 4 that results in a nonconservative amino mitted. To allow inclusion of families with missing data for a acid substitution of Arg/Thr at amino acid 260 (ref SNP ID: single parent, the Transmit program http://www- rs2071888) [9,10]. Three intronic polymorphisms of TPSN gene.cimr.cam.ac.uk/clayton/software/[15], which uses have also been described, none of which appear to be in population allele frequencies to weight the possible paren- linkage disequilibrium (LD) with HLA class I alleles or the tal genotypes, was used for the TDT analysis. In the Trans- extended HLA-A1, HLA-B8, HLA-DR3 haplotype, in at mit program, genotypes of unaffected siblings (or siblings least one healthy Caucasian population [11]. Furthermore, whose disease status is unknown) are used to infer paren- using a large UK Caucasian sample, Ahmad and coworkers tal genotypes, thus increasing the power to detect associ- [12] recently reported that TPSN polymorphisms are not in ation. We applied this test first to the combined US and the LD with more telomeric MHC haplotypes. In the present UK data and then to each set separately. The significance study we report an association between the exon 4 TPSN level of the combined results was also calculated using polymorphism and susceptibility to SoJRA, involving the Fisher's method of combining P values for two independent TPSN allele Arg260 (01 allele). analyses that test the same hypothesis. LD between TPSN and the HLA region (limited to the Cincinnati cohort) was Methods evaluated using the EH program http://linkage.rockefel The study cohort included 88 SoJRA affected families ler.edu/ott/eh.htm[16,17]. The Geno-Pdt test in the PdT recruited in Cincinnati (US cohort) and 74 simplex (with 5.1 program http://wwwchg.duhs.duke.edu/software/ one affected offspring) SoJRA families identified by the pdt.html was also used as a test for association and linkage British Paediatric Rheumatology Study Group (UK cohort). in the US SoJRA-affected families [18-20]. Unaffected siblings were available for analysis in the US but not in the UK cohort. An additional 113 healthy unre- Results lated control individuals, primarily Caucasians from the Mid- The distribution of tapasin genotypes among SoJRA- west and New England, resembled the SoJRA-affected affected children was compared with that in their healthy families in terms ethnicity and served as the control popu- siblings, as well as with that in unrelated healthy control lation. Ethics approvals were obtained from the participat- individuals using a two degrees of freedom χ2 test in the US ing institutions, and informed consent was obtained from cohort (Table 1). The differences did not reach statistical parents and/or children. significance. The allelic frequencies of tapasin in the inde- pendent cohorts from the USA (Table 1) were in Hardy– All affected children met American College of Rheumatol- Weinberg equilibrium (healthy individuals from the USA: χ2 ogy criteria for a diagnosis of JRA; they were subgrouped = 0.3049, P = 0.58; SoJRA-affected individuals
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