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HLA-DRB1, TAP2/TAP1, and HLA-DPB1 haplotypes in Finnish juvenile idiopathic arthritis: more complexity within the MHC

Genes & Immunity volume 5, pages 562–571 (2004)Cite this article

Abstract

This study further defines genetic susceptibility to JIA in the region centromeric to HLA-DRB1. DNA from 234 Finnish JIA nuclear families and 639 elderly Finnish control individuals was genotyped for five functional SNPs within the TAP2 and TAP1 loci (∼200 kb centromeric of HLA-DRB1). Subsets of the controls (186) and patients (145) that had been previously typed for HLA-DRB1 were also genotyped by sequence for the HLA-DPB1 locus. Case/control and transmission disequilibrium test (TDT) methods revealed an association with the DPB1*030101 allele for JIA (OR 2.3, 95% CI 1.5–3.5). Notably, a detailed haplotypic analysis of the TAP2/TAP1 loci and their interaction with the HLA-DPB1*030101 and DRB1*08 and *11 alleles showed a variety of over-represented and under-represented TAP2/TAP1 haplotypes not evident in the single marker analysis. The strongest effect was observed in the polyarticular RF negative JIA subgroup for the 2-2-1-2-1 TAP2/TAP1 haplotype (TAP2B and TAP1A alleles) which showed an independent effect from both DRB1*08 and *11 (P<0.000003) and DPB1*030101 (P=0.02). We have provided evidence that the extended haplotypes (including HLA-DRB1, TAP2/TAP1, and HLA-DPB1) of pauciarticular and polyarticular RF negative disease are distinct. This observation may have implications for functional etiological differences between the pauciarticular and polyarticular JIA patients.

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References

  1. Glass DN, Giannini EH . Juvenile rheumatoid arthritis as a complex genetic trait. Arthritis Rheum 1999; 42: 2261–2268.

    Article  CAS  Google Scholar 

  2. Førre Ø, Smerdel A . Genetic epidemiology of juvenile idiopathic arthritis. Scand J Rheumatol 2002; 31: 123–128.

    Article  Google Scholar 

  3. Albert ED, Scholz S . Juvenile arthritis: genetic update. Baillieres Clin Rheumatol 1998; 12: 209–218.

    Article  CAS  Google Scholar 

  4. Petty RE, Southwood TR, Baum J et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998; 25: 1991–1994.

    CAS  PubMed  Google Scholar 

  5. Barron KS, Silverman ED, Gonzales JC, Owerbach D, Reveille JD . DNA analysis of HLA-DR, DQ, and DP alleles in children with polyarticular juvenile rheumatoid arthritis. J Rheumatol 1992; 19: 1611–1616.

    CAS  PubMed  Google Scholar 

  6. Barron KS, Joseph AK, Macleod M, Gonzales JC, Owerbach D, Reveille JD . DNA analysis of HLA-DR, DQ and DP genes in pauciarticular juvenile rheumatoid arthritis. J Rheumatol 1991; 18: 1723–1729.

    CAS  PubMed  Google Scholar 

  7. Paul C, Schoenwald U, Truckenbrodt H et al. HLA-DP/DR interaction in early onset pauciarticular juvenile chronic arthritis. Immunogenetics 1993; 37: 442–448.

    Article  CAS  Google Scholar 

  8. Paul C, Haas JP, Schoenwald U et al. HLA class I/class II interaction in early onset pauciarticular juvenile chronic arthritis. Immunogenetics 1994; 39: 61–64.

    Article  CAS  Google Scholar 

  9. Paul C, Yao Z, Nevinny-Stickel C et al. Immunogenetics of juvenile chronic arthritis. I. HLA interaction between A2, DR5/8-DR/DQ, and DPB1*0201 is a general feature of all subsets of early onset pauciarticular juvenile chronic arthritis II. DPB1 polymorphism plays a role in systemic juvenile chronic arthritis. Tissue Antigens 1995; 45: 280–283.

    Article  CAS  Google Scholar 

  10. Ploski R, McDowell TL, Symons JA et al. Interaction between HLA-DR and HLA-DP, and between HLA and interleukin 1 alpha in juvenile rheumatoid arthritis indicates heterogeneity of pathogenic mechanisms of the disease. Hum Immunol 1995; 42: 343–347.

    Article  CAS  Google Scholar 

  11. Ploski R, Flato B, Vinje O, Maksymowych W, Førre Ø, Thorsby E . Association to HLA-DRB1*08, HLA-DPB1*0301 and homozygosity for an HLA-linked proteasome gene in juvenile ankylosing spondylitis. Hum Immunol 1995; 44: 88–96.

    Article  CAS  Google Scholar 

  12. Fernandez-Viña MA, Fink CW, Stastny P . HLA antigens in juvenile arthritis. Pauciarticular and polyarticular juvenile arthritis are immunogenetically distinct. Arthritis Rheum 1990; 33: 1787–1794.

    Article  Google Scholar 

  13. Begovich AB, Bugawan TL, Nepom BS, Klitz W, Nepom GT, Erlich HA . A specific HLA-DP beta allele is associated with pauciarticular juvenile rheumatoid arthritis but not adult rheumatoid arthritis. Proc Natl Acad Sci USA 1989; 86: 9489–9493.

    Article  CAS  Google Scholar 

  14. Cerna M, Vavrincova P, Havelka S, Ivaskova E, Stastny P . Class II alleles in juvenile arthritis in Czech children. J Rheumatol 1994; 21: 159–164.

    CAS  PubMed  Google Scholar 

  15. Ploski R, Vinje O, Rønningen KS et al. HLA class II alleles and heterogeneity of juvenile rheumatoid arthritis. DRB1*0101 may define a novel subset of the disease. Arthritis Rheum 1993; 36: 465–472.

    Article  CAS  Google Scholar 

  16. Prahalad S, Kingsbury DJ, Griffin TA et al. Polymorphism in the MHC-encoded LMP7 gene: association with JRA without functional significance for immunoproteasome assembly. J Rheumatol 2001; 28: 2320–2325.

    CAS  Google Scholar 

  17. Pryhuber KG, Murray KJ, Donnelly P et al. Polymorphism in the LMP2 gene influences disease susceptibility and severity in HLA-B27 associated juvenile rheumatoid arthritis. J Rheumatol 1996; 23: 747–752.

    CAS  PubMed  Google Scholar 

  18. Donn RP, Davies EJ, Holt PL, Thomson W, Ollier W . Increased frequency of TAP2B in early onset pauciarticular juvenile chronic arthritis. Ann Rheum Dis 1994; 53: 261–264.

    Article  CAS  Google Scholar 

  19. Ploski R, Undlien DE, Vinje O, Førre Ø, Thorsby E, Ronningen KS . Polymorphism of human major histocompatibility complex-encoded transporter associated with antigen processing (TAP) genes and susceptibility to juvenile rheumatoid arthritis. Hum Immunol 1994; 39: 54–60.

    Article  CAS  Google Scholar 

  20. Fernandez-Viña MA, Fink C, Sang S, Stastny P . Peptide transporter genes in susceptibility to juvenile arthritis. Hum Immunol 1993; 37 (Suppl 1): 58.

    Google Scholar 

  21. Runstadler JA, Säilä H, Savolainen A et al. Analysis of MHC region genetics in Finnish patients with juvenile idiopathic arthritis: evidence for different locus-specific effects in polyarticular vs pauciarticular subsets and a shared DRB1 epitope. Genes Immun 2003; 4: 326–335.

    Article  CAS  Google Scholar 

  22. Gao X, Fernandez-Viña M, Olsen NJ, Pincus T, Stastny P . Hla-Dpb1 0301 is a major risk factor for rheumatoid factor-negative adult rheumatoid arthritis. Arthritis Rheum 1991; 34: 1310–1312.

    Article  CAS  Google Scholar 

  23. Donn RP, Thomson W, Pepper L et al. Antinuclear antibodies in early onset pauciarticular juvenile chronic arthritis (JCA) are associated with HLA-DQB1*0603: a possible JCA-associated human leucocyte antigen haplotype. Br J Rheum 1995; 34: 461–465.

    Article  CAS  Google Scholar 

  24. Morling N, Friis J, Fugger L et al. DNA polymorphism of HLA class II genes in pauciarticular juvenile rheumatoid arthritis. Tissue Antigens 1991; 38: 16–23.

    Article  CAS  Google Scholar 

  25. Murray K, Thompson SD, Glass DN . Pathogenesis of juvenile chronic arthritis: genetic and environmental factors. Arch Dis Childhood 1997; 77: 530–534.

    Article  CAS  Google Scholar 

  26. Van Kerckhove C, Luyrink L, Elma MS et al. HLA-DP/DR interaction in children with juvenile rheumatoid arthritis. Immunogenetics 1990; 32: 364–368.

    Article  CAS  Google Scholar 

  27. Carrington M, Colonna M, Spies T, Stephens JC, Mann DL . Haplotypic variation of the transporter associated with antigen processing (TAP) genes and their extension of HLA class II region haplotypes. Immunogenetics 1993; 37: 266–273.

    Article  CAS  Google Scholar 

  28. Colonna M, Bresnahan M, Bahram S, Strominger JL, Spies T . Allelic variants of the human putative peptide transporter involved in antigen processing. Proc Natl Acad Sci USA 1992; 89: 3932–3936.

    Article  CAS  Google Scholar 

  29. Powis SH, Tonks S, Mockridge I, Kelly AP, Bodmer JG, Trowsdale J . Alleles and haplotypes of the MHC-encoded ABC transporters TAP1 and TAP2. Immunogenetics 1993; 37: 373–380.

    Article  CAS  Google Scholar 

  30. Smerdel A, Lie BA, Ploski R et al. A gene in the telomeric HLA complex distinct from HLA-A is involved in predisposition to juvenile idiopathic arthritis. Arthritis Rheum 2002; 46: 1614–1619.

    Article  CAS  Google Scholar 

  31. Klitz W, Stephens JC, Grote M, Carrington M . Discordant patterns of linkage disequilibrium of the peptide-transporter loci within the HLA class II region. Am J Hum Genet 1995; 57: 1436–1444.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Jeffreys AJ, Ritchie A, Neumann R . High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum Mol Genet 2000; 9: 725–733.

    Article  CAS  Google Scholar 

  33. Cullen M, Erlich H, Klitz W, Carrington M . Molecular mapping of a recombination hotspot located in the second intron of the human TAP2 locus. Am J Hum Genet 1995; 56: 1350–1358.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bali D, Gourley S, Kostyu DD et al. Genetic analysis of multiplex rheumatoid arthritis families. Genes Immun 1999; 1: 28–36.

    Article  CAS  Google Scholar 

  35. Brewer Jr EJ, Bass J, Baum J et al. Current proposed revision of JRA Criteria. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Section of The Arthritis Foundation. Arthritis Rheum 1977; 20 (Suppl 2): 195–199.

    Google Scholar 

  36. Sham PC, Curtis D . Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59 (Part 1): 97–105.

    Article  CAS  Google Scholar 

  37. Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19 (Suppl 1): S36–S42.

    Article  Google Scholar 

  38. Horvath S, Xu X, Laird NM . The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001; 9: 301–306.

    Article  CAS  Google Scholar 

  39. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  Google Scholar 

  40. Svejgaard A, Ryder LP . HLA and disease associations: detecting the strongest association. Tissue Antigens 1994; 43: 18–27.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Dr Runstadler was supported by an NRSA postdoctoral fellowship as a part of the training grant in Comparative Medicine at the University of California, Davis. This work was supported in part by NIH Grant #AR44422, the Academy of Finland (Grant 46558), the Päivikki and Sakari Sohlberg Foundation, the EVO funds of the Rheumatism Association Hospital, and the Helsinki University Central Hospital Research Fund.

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Authors and Affiliations

  1. Departments of Biological Chemistry and Medicine, Rowe Program in Human Genetics and Molecular Medicine, University of California, Davis, USA

    JA Runstadler & M F Seldin

  2. Rheumatism Foundation Hospital, Heinola, Finland

    H Säilä & A Savolainen

  3. Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    M Leirisalo-Repo

  4. National Public Health Institute, Helsinki, Finland

    K Aho, E Tuomilehto-Wolf & J Tuomilehto

  5. Department of Public Health, University of Helsinki, Helsinki, Finland

    J Tuomilehto

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  1. JA Runstadler
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  2. H Säilä
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Correspondence to JA Runstadler.

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Runstadler, J., Säilä, H., Savolainen, A. et al. HLA-DRB1, TAP2/TAP1, and HLA-DPB1 haplotypes in Finnish juvenile idiopathic arthritis: more complexity within the MHC. Genes Immun 5, 562–571 (2004). https://doi.org/10.1038/sj.gene.6364129

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