title: Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case-control study.
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 (chi2 = 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.
authors.affiliation: William S, Rowe Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. hxb38@case.edu
authors.forename: Hulya
authors.initials: H
authors.lastname: Bukulmez
authors.forename: Mark
authors.initials: M
authors.lastname: Fife
authors.forename: Monica
authors.initials: M
authors.lastname: Tsoras
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Twine
authors.forename: Patricia
authors.initials: P
authors.lastname: Woo
authors.forename: Jane M
authors.initials: JM
authors.lastname: Olson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.forename: David N
authors.initials: DN
authors.lastname: Glass
authors.forename: Robert A
authors.initials: RA
authors.lastname: Colbert
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D017920:Antiporters / Q000235:genetics*; D001171:Arthritis, Juvenile / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D026901:Membrane Transport Proteins; D020125:Mutation, Missense; D017354:Point Mutation; D011110:Polymorphism, Genetic; D035781:Siblings; D044465:White People / Q000235:genetics
chemical_list: D017920:Antiporters; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; C107762:tapasin
references.citation: Arthritis Rheum. 1999 Nov;42(11):2261-8
references.pmid: 10555018
references.citation: Clin Exp Rheumatol. 1992 Mar-Apr;10(2):189-93
references.pmid: 1505114
references.citation: Am J Hum Genet. 2000 Jul;67(1):146-54
references.pmid: 10825280
references.citation: Am J Hum Genet. 1999 Oct;65(4):1170-7
references.pmid: 10486336
references.citation: Immunogenetics. 2000 Nov;52(1-2):9-11
references.pmid: 11132161
references.citation: Arthritis Rheum. 2001 Apr;44(4):802-10
references.pmid: 11315919
references.citation: Nat Cell Biol. 2001 Aug;3(8):708-14
references.pmid: 11483955
references.citation: Hum Mol Genet. 2003 Mar 15;12(6):647-56
references.pmid: 12620970
references.citation: J Pediatr. 2003 Mar;142(3):292-6
references.pmid: 12640378
references.citation: Genet Epidemiol. 2003 Nov;25(3):203-13
references.pmid: 14557988
references.citation: Am J Hum Genet. 2003 Nov;73(5):1016-26
references.pmid: 14551902
references.citation: Arthritis Rheum. 1980 Jul;23(7):796-9
references.pmid: 7406930
references.citation: Arthritis Rheum. 1985 Feb;28(2):146-50
references.pmid: 3970730
references.citation: Genet Epidemiol. 1989;6(1):127-30
references.pmid: 2731704
references.citation: Am J Hum Genet. 1993 Mar;52(3):506-16
references.pmid: 8447318
references.citation: Br J Rheumatol. 1995 May;34(5):454-60
references.pmid: 7788176
references.citation: Tissue Antigens. 1995 Apr;45(4):280-3
references.pmid: 7638866
references.citation: Rev Rhum Engl Ed. 1996 Mar;63(3):163-70
references.pmid: 8731233
references.citation: Am J Hum Genet. 1996 Nov;59(5):983-9
references.pmid: 8900224
references.citation: Cell. 1997 Jun 27;89(7):1067-76
references.pmid: 9215629
references.citation: Eur J Immunol. 1998 Feb;28(2):459-67
references.pmid: 9521053
references.citation: J Mol Biol. 1998 Apr 10;277(4):839-57
references.pmid: 9545376
references.citation: Annu Rev Immunol. 1998;16:323-58
references.pmid: 9597133
references.citation: J Clin Invest. 1998 Oct 1;102(7):1369-76
references.pmid: 9769329
references.citation: Arthritis Rheum. 1999 Sep;42(9):1843-53
references.pmid: 10513798
references.citation: Arthritis Rheum. 1999 Dec;42(12):2577-82
references.pmid: 10616003