Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

A review of the MHC genetics of rheumatoid arthritis

Abstract

Rheumatoid arthritis is a common complex genetic disease, and, despite a significant genetic element, no gene other than HLA-DRB1 has been clearly demonstrated to be involved in the disease. However, this association accounts for less than half the overall genetic susceptibility. Investigation of other candidate genes, in particular those that reside within the major histocompatibility complex, are hampered by the presence of strong linkage disequilibrium and problems with study design.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Silman AJ, MacGregor AJ, Thomson W et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 1993; 32: 903–907.

    Article  CAS  PubMed  Google Scholar 

  2. Aho K, Koskenvuo M, Tuominen J, Kaprio J . Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol 1986; 13: 899–902.

    CAS  PubMed  Google Scholar 

  3. Lawrence JS . The epidemiology and genetics of rheumatoid arthritis. Rheumatology 1969; 2: 1–36.

    CAS  PubMed  Google Scholar 

  4. Silman AJ . Problems complicating the genetic epidemiology of rheumatoid arthritis. J Rheumatol 1997; 24: 194–196.

    CAS  PubMed  Google Scholar 

  5. Milner CM, Campbell RD . Genetic organization of the human MHC class III region. Front Biosci 2001; 6: D914–D926.

    Article  CAS  PubMed  Google Scholar 

  6. Stastny P . Mixed lymphocyte cultures in rheumatoid arthritis. J Clin Invest 1976; 57: 1148–1157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gregersen PK, Silver J, Winchester RJ . The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30: 1205–1213.

    Article  CAS  PubMed  Google Scholar 

  8. Milicic A, Lee D, Brown MA, Darke C, Wordsworth BP . HLA-DR/DQ haplotype in rheumatoid arthritis: novel allelic associations in UK Caucasians. J Rheumatol 2002; 29: 1821–1826.

    CAS  PubMed  Google Scholar 

  9. Rigby AS, Silman AJ, Voelm L et al. Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred. Genet Epidemiol 1991; 8: 153–175.

    Article  CAS  PubMed  Google Scholar 

  10. Rigby AS, Voelm L, Silman AJ . Epistatic modeling in rheumatoid arthritis: an application of the Risch theory. Genet Epidemiol 1993; 10: 311–320.

    Article  CAS  PubMed  Google Scholar 

  11. Genin E, Babron MC, McDermott MF et al. Modelling the major histocompatibility complex susceptibility to RA using the MASC method. Genet Epidemiol 1998; 15: 419–430.

    Article  CAS  PubMed  Google Scholar 

  12. Gough A, Faint J, Salmon M et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum 1994; 37: 1166–1170.

    Article  CAS  PubMed  Google Scholar 

  13. MacGregor A, Ollier W, Thomson W, Jawaheer D, Silman A . HLA-DRB1*0401/0404 genotype and rheumatoid arthritis: increased association in men, young age at onset, and disease severity. J Rheumatol 1995; 22: 1032–1036.

    CAS  PubMed  Google Scholar 

  14. Wordsworth P, Pile KD, Buckely JD et al. HLA heterozygosity contributes to susceptibility to rheumatoid arthritis. Am J Hum Genet 1992; 51: 585–591.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hall FC, Weeks DE, Camilleri JP et al. Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis. QJM 1996; 89: 821–829.

    Article  CAS  PubMed  Google Scholar 

  16. Deighton CM, Walker DJ, Griffiths ID, Roberts DF . The contribution of HLA to rheumatoid arthritis. Clin Genet 1989; 36: 178–182.

    Article  CAS  PubMed  Google Scholar 

  17. Nepom GT, Nepom BS . Prediction of susceptibility to rheumatoid arthritis by human leukocyte antigen genotyping. Rheum Dis Clin N Am 1992; 18: 785–792.

    CAS  Google Scholar 

  18. Nabozny GH, Baisch JM, Cheng S et al. HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: a novel model for human polyarthritis. J Exp Med 1996; 183: 27–37.

    Article  CAS  PubMed  Google Scholar 

  19. Bradley DS, Nabozny GH, Cheng S et al. HLA-DQB1 polymorphism determines incidence, onset, and severity of collagen-induced arthritis in transgenic mice. Implications in human rheumatoid arthritis. J Clin Invest 1997; 100: 2227–2234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Taneja V, Griffiths MM, Luthra H, David CS . Modulation of HLA-DQ-restricted collagen-induced arthritis by HLA-DRB1 polymorphism. Int Immunol 1998; 10: 1449–1457.

    Article  CAS  PubMed  Google Scholar 

  21. Zanelli E, Krco CJ, David CS . Critical residues on HLA-DRB1*0402 HV3 peptide for HLA-DQ8-restricted immunogenicity: implications for rheumatoid arthritis predisposition. J Immunol 1997; 158: 3545–3551.

    CAS  PubMed  Google Scholar 

  22. Zanelli E, Breedveld FC, de Vries RR . HLA association with autoimmune disease: a failure to protect? Rheumatology (Oxford) 2000; 39: 1060–1066.

    Article  CAS  Google Scholar 

  23. van der Horst-Bruinsma IE, Visser H, Hazes JM et al. HLA-DQ-associated predisposition to and dominant HLA-DR-associated protection against rheumatoid arthritis. Hum Immunol 1999; 60: 152–158.

    Article  CAS  PubMed  Google Scholar 

  24. de Vries N, van Elderen C, Tijssen H, van Riel PL, van de Putte LB . No support for HLA-DQ encoded susceptibility in rheumatoid arthritis. Arthritis Rheum 1999; 42: 1621–1627.

    Article  CAS  PubMed  Google Scholar 

  25. Cranney A, Goldstein R, Pham B, Newkirk MM, Karsh J . A measure of limited joint motion and deformity correlates with HLA-DRB1 and DQB1 alleles in patients with rheumatoid arthritis. Ann Rheum Dis 1999; 58: 703–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lanchbury JS, Jaeger EE, Sansom DM et al. Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome. Hum Immunol 1991; 32: 56–64.

    Article  CAS  PubMed  Google Scholar 

  27. Hajeer AH, Dababneh A, Makki RF et al. Different gene loci within the HLA-DR and TNF regions are independently associated with susceptibility and severity in Spanish rheumatoid arthritis patients. Tissue Antigens 2000; 55: 319–325.

    Article  CAS  PubMed  Google Scholar 

  28. Martinez A, Fernandez-Arquero M, Pascual-Salcedo D et al. Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis. Arthritis Rheum 2000; 43: 1366–1370.

    Article  CAS  PubMed  Google Scholar 

  29. Plevy SE, Targan SR, Yang H, Fernandez D, Rotter JI, Toyoda H . Tumor necrosis factor microsatellites define a Crohn's disease-associated haplotype on chromosome 6. Gastroenterology 1996; 110: 1053–1060.

    Article  CAS  PubMed  Google Scholar 

  30. Waldron-Lynch F, Adams C, Amos C et al. Tumour necrosis factor 5′ promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families. Genes Immun 2001; 2: 82–87.

    Article  CAS  PubMed  Google Scholar 

  31. Lie BA, Ronningen KS, Akselsen HE, Thorsby E, Undlien DE . Application and interpretation of transmission/disequilibrium tests: transmission of HLA-DQ haplotypes to unaffected siblings in 526 families with type 1 diabetes. Am J Hum Genet 2000; 66: 740–743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Koeleman BP, Dudbridge F, Cordell HJ, Todd JA . Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the conditional extended transmission/disequilibrium test. Ann Hum Genet 2000; 64: 207–213.

    Article  CAS  PubMed  Google Scholar 

  33. 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  PubMed  PubMed Central  Google Scholar 

  34. Newton J, Brown MA, Milicic A et al. The effect of HLA-DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin alpha-tumor necrosis factor haplotype. Arthritis Rheum 2003; 48: 90–96.

    Article  CAS  PubMed  Google Scholar 

  35. Zanelli E, Jones G, Pascual M et al. The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci. Hum Immunol 2001; 62: 75–84.

    Article  CAS  PubMed  Google Scholar 

  36. Jawaheer D, Gregersen PK . Rheumatoid arthritis. The genetic components. Rheum Dis Clin North Am 2002; 28: 1–15.

    Article  PubMed  Google Scholar 

  37. Okamoto K, Makino K, Yoshikawa Y et al. Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am J Hum Genet 2003; 72: 303–312.

    Article  CAS  PubMed  Google Scholar 

  38. Jawaheer D, Li W, Graham RR et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 2002; 71: 585–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Singal DP, Li J, Lei K . Genetics of rheumatoid arthritis (RA): two separate regions in the major histocompatibility complex contribute to susceptibility to RA. Immunol Lett 1999; 69: 301–306.

    Article  CAS  PubMed  Google Scholar 

  40. ten Wolde S, Breedveld FC, de Vries RR et al. Influence of non-inherited maternal HLA antigens on occurrence of rheumatoid arthritis. Lancet 1993; 341: 200–202.

    Article  CAS  PubMed  Google Scholar 

  41. Barrera P, Balsa A, Alves H et al. Noninherited maternal antigens do not play a role in rheumatoid arthritis susceptibility in Europe. European Consortium on Rheumatoid Arthritis Families. Arthritis Rheum 2000; 43: 758–764.

    Article  CAS  PubMed  Google Scholar 

  42. Barrera P, Balsa A, Alves H et al. Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF). J Rheumatol 2001; 28: 968–974.

    CAS  PubMed  Google Scholar 

  43. Harney S, Newton J, Milicic A, Brown MA, Wordsworth BP . Non-inherited maternal HLA alleles are associated with rheumatoid arthritis. Rheumatology (Oxford) 2003; 42: 171–174.

    Article  CAS  Google Scholar 

  44. Angelini G, Morozzi G, Delfino L et al. Analysis of HLA DP, DQ, and DR alleles in adult Italian rheumatoid arthritis patients. Hum Immunol 1992; 34: 135–141.

    Article  CAS  PubMed  Google Scholar 

  45. Perdriger A, Semana G, Quillivic F et al. DPB1 polymorphism in rheumatoid arthritis: evidence of an association with allele DPB1 0401. Tissue Antigens 1992; 39: 14–18.

    Article  CAS  PubMed  Google Scholar 

  46. Brinkman BM, Giphart MJ, Verhoef A et al. Tumor necrosis factor alpha-308 gene variants in relation to major histocompatibility complex alleles and Felty's syndrome. Hum Immunol 1994; 41: 259–266.

    Article  CAS  PubMed  Google Scholar 

  47. Vandevyver C, Raus P, Stinissen P, Philippaerts L, Cassiman JJ, Raus J . Polymorphism of the tumour necrosis factor beta gene in multiple sclerosis and rheumatoid arthritis. Eur J Immunogenet 1994; 21: 377–382.

    Article  CAS  PubMed  Google Scholar 

  48. Singal DP, Ye M, Qiu X, D'Souza M . Polymorphisms in the TAP2 gene and their association with rheumatoid arthritis. Clin Exp Rheumatol 1994; 12: 29–33.

    CAS  PubMed  Google Scholar 

  49. Wilson AG, de Vries N, van de Putte LB, Duff GW . A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis. Ann Rheum Dis 1995; 54: 601–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vandevyver C, Geusens P, Cassiman JJ, Raus J . Peptide transporter genes (TAP) polymorphisms and genetic susceptibility to rheumatoid arthritis. Br J Rheumatol 1995; 34: 207–214.

    Article  CAS  PubMed  Google Scholar 

  51. Maksymowych WP, Tao S, Luong M et al. Polymorphism in the LMP2 and LMP7 genes and adult rheumatoid arthritis: no relationship with disease susceptibility or outcome. Tissue Antigens 1995; 46: 136–139.

    Article  CAS  PubMed  Google Scholar 

  52. Wordsworth BP, Pile KD, Gibson K, Burney RO, Mockridge I, Powis SH . Analysis of the MHC-encoded transporters TAP1 and TAP2 in rheumatoid arthritis: linkage with DR4 accounts for the association with a minor TAP2 allele. Tissue Antigens 1993; 42: 153–155.

    Article  CAS  PubMed  Google Scholar 

  53. Mulcahy B, Waldron-Lynch F, McDermott MF et al. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet 1996; 59: 676–683.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hillarby MC, Davies EJ, Donn RP, Grennan DM, Ollier WE . TAP2D is associated with HLA-B44 and DR4 and may contribute to rheumatoid arthritis and Felty's syndrome susceptibility. Clin Exp Rheumatol 1996; 14: 67–70.

    CAS  PubMed  Google Scholar 

  55. Field M, Gallagher G, Eskdale J et al. Tumor necrosis factor locus polymorphisms in rheumatoid arthritis. Tissue Antigens 1997; 50: 303–307.

    Article  CAS  PubMed  Google Scholar 

  56. Brinkman BM, Huizinga TW, Kurban SS et al. Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? Br J Rheumatol 1997; 36: 516–521.

    Article  CAS  PubMed  Google Scholar 

  57. Vinasco J, Beraun Y, Nieto A et al. Polymorphism at the TNF loci in rheumatoid arthritis. Tissue Antigens 1997; 49: 74–78.

    Article  CAS  PubMed  Google Scholar 

  58. Vinasco J, Beraun Y, Nieto A et al. Heat shock protein 70 gene polymorphisms in rheumatoid arthritis. Tissue Antigens 1997; 50: 71–73.

    Article  CAS  PubMed  Google Scholar 

  59. Singal DP, Li J, Ye M, Lei K . D6S273 microsatellite polymorphism and susceptibility to rheumatoid arthritis. Tissue Antigens 1998; 52: 353–358.

    Article  CAS  PubMed  Google Scholar 

  60. Tuokko J, Pushnova E, Yli-Kerttula U, Toivanen A, Ilonen J . TAP2 alleles in inflammatory arthritis. Scand J Rheumatol 1998; 27: 225–229.

    Article  CAS  PubMed  Google Scholar 

  61. Vinasco J, Fraile A, Nieto A et al. Analysis of LMP and TAP polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in rheumatoid arthritis. Ann Rheum Dis 1998; 57: 33–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. van Krugten MV, Huizinga TW, Kaijzel EL et al. Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis. Genes Immun 1999; 1: 91–96.

    Article  CAS  PubMed  Google Scholar 

  63. Waldron-Lynch F, Adams C, Shanahan F, Molloy MG, O'Gara F . Genetic analysis of the 3′ untranslated region of the tumour necrosis factor shows a highly conserved region in rheumatoid arthritis affected and unaffected subjects. J Med Genet 1999; 36: 214–216.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Seki N, Kamizono S, Yamad A et al. Polymorphisms in the 5′-flanking region of tumor necrosis factor-alpha gene in patients with rheumatoid arthritis. Tissue Antigens 1999; 54: 194–197.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Perdriger A, Guggenbuhl P, Chales G et al. Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis. Rheumatology (Oxford) 1999; 38: 448–452.

    Article  CAS  Google Scholar 

  67. Singal DP, Ye M, Buchanan WW, Qiu X . HLA-D region genes and susceptibility to rheumatoid arthritis. Transplant Proc 1997; 29: 1126.

    Article  CAS  PubMed  Google Scholar 

  68. Shibue T, Tsuchiya N, Komata T et al. Tumor necrosis factor alpha 5′-flanking region, tumor necrosis factor receptor II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis. Arthritis Rheum 2000; 43: 753–757.

    Article  CAS  PubMed  Google Scholar 

  69. Singal DP, Li J, Zhu Y . HLA class III region and susceptibility to rheumatoid arthritis. Clin Exp Rheumatol 2000; 18: 485–491.

    CAS  PubMed  Google Scholar 

  70. Vejbaesya S, Luangtrakool P, Luangtrakool K, Sermduangprateep C, Parivisutt L . Analysis of TAP and HLA-DM polymorphism in Thai rheumatoid arthritis. Hum Immunol 2000; 61: 309–313.

    Article  CAS  PubMed  Google Scholar 

  71. Jenkins SC, March RE, Campbell RD, Milner CM . A novel variant of the MHC-linked hsp70, hsp70-hom, is associated with rheumatoid arthritis. Tissue Antigens 2000; 56: 38–44.

    Article  CAS  PubMed  Google Scholar 

  72. Castro F, Acevedo E, Ciusani E et al. Tumour necrosis factor microsatellites and HLA-DRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients with rheumatoid arthritis. Ann Rheum Dis 2001; 60: 791–795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hadj Kacem H, Kaddour N, Adyel FZ, Bahloul Z, Ayadi H . HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and CTLA-4 polymorphisms in Tunisian patients with rheumatoid arthritis and Sjogren's syndrome. Rheumatology (Oxford) 2001; 40: 1370–1374.

    Article  CAS  Google Scholar 

  74. Ota M, Katsuyamana Y, Kimura A et al. A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region. Genomics 2001; 71: 263–270.

    Article  CAS  PubMed  Google Scholar 

  75. Tuokko J, Nejentsev S, Luukkainen R, Toivanen A, Ilonen J . HLA haplotype analysis in Finnish patients with rheumatoid arthritis. Arthritis Rheum 2001; 44: 315–322.

    Article  CAS  PubMed  Google Scholar 

  76. Singal DP, Li J, Zhang G . Microsatellite polymorphism of the MICA gene and susceptibility to rheumatoid arthritis. Clin Exp Rheumatol 2001; 19: 451–452.

    CAS  PubMed  Google Scholar 

  77. Martinez A, Fernandez-Arquero M, Balsa A et al. Primary association of a MICA allele with protection against rheumatoid arthritis. Arthritis Rheum 2001; 44: 1261–1265.

    Article  CAS  PubMed  Google Scholar 

  78. Low AS, Gonzalez-Gay MA, Akil M et al. TNF +489 polymorphism does not contribute to susceptibility to rheumatoid arthritis. Clin Exp Rheumatol 2002; 20: 829–832.

    CAS  PubMed  Google Scholar 

  79. Udalova IA, Richardson A, Ackerman H, Wordsworth P, Kwiatkowski D . Association of accelerated erosive rheumatoid arthritis with a polymorphism that alters NF-kappaB binding to the TNF promoter region. Rheumatology (Oxford) 2002; 41: 830–831.

    Article  CAS  Google Scholar 

  80. Cvetkovic JT, Wallberg-Jonsson S, Stegmayr B, Rantapaa-Dahlqvist S, Lefvert AK . Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes. J Rheumatol 2002; 29: 212–219.

    CAS  PubMed  Google Scholar 

  81. Pascual M, Mataran L, Jones G et al. HLA haplotypes and susceptibility to rheumatoid arthritis. More than class II genes. Scand J Rheumatol 2002; 31: 275–278.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to MA Brown.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Newton, J., Harney, S., Wordsworth, B. et al. A review of the MHC genetics of rheumatoid arthritis. Genes Immun 5, 151–157 (2004). https://doi.org/10.1038/sj.gene.6364045

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364045

Keywords

This article is cited by

Search

Quick links