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:

Rheumatoid arthritis: a view of the current genetic landscape

Genes & Immunity volume 10, pages 101–111 (2009)Cite this article

Abstract

The field of genetics and autoimmune diseases is undergoing a rapid and unprecedented expansion with new genetic findings being reported at an astounding pace. It is now clear that multiple genes contribute to each of the major autoimmune disorders, with significant genetic overlaps among them. Rheumatoid arthritis (RA) is no exception to this, and emerging data are beginning to reveal the outlines of new diagnostic subgroups, complex overlapping relationships with other autoimmune disorders and potential new targets for therapy. This review describes the evolving genetic landscape of RA, with the full knowledge that our current view is far from complete. However, with the first round of genome-wide association scans now completed, it is reasonable to begin to take stock of the direction in which the major common genetic risk factors are leading us.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Oliver JE, Silman AJ . Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol 2006; 35: 169–174.

    Google Scholar 

  2. Firestein GS . Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–361.

    Google Scholar 

  3. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.

    Google Scholar 

  4. Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155–163.

    Google Scholar 

  5. Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

    Google Scholar 

  6. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J med 2007; 357: 1199–1209.

    Google Scholar 

  7. Amos CI, Chen WV, Lee A, Li W, Kern M, Lundsten R et al. High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33. Genes Immun 2006; 7: 277–286.

    Google Scholar 

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

    Google Scholar 

  9. Nepom GT . Major histocompatibility complex-directed susceptibility to rheumatoid arthritis. Adv Immunol 1998; 68: 315–332.

    Google Scholar 

  10. Ding B, Padyukov L, Lundstrum E, Seielstad M, Plenge RM, Oksenberg JR et al. Different patterns of associations with ACPA-positive and ACPA-negative rheumatoid arthritis in the extended MHC region. Arthritis Rheum 2008 (in press).

  11. Stastny P . Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978; 298: 869–871.

    Google Scholar 

  12. 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.

    Google Scholar 

  13. van Gaalen FA, van Aken J, Huizinga TW, Schreuder GM, Breedveld FC, Zanelli E et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum 2004; 50: 2113–2121.

    Google Scholar 

  14. Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum 2005; 52: 3813–3818.

    Google Scholar 

  15. Mozes E, McDevitt HO, Jaton JC, Sela M . The genetic control of antibody specificity. J Exp Med 1969; 130: 1263–1278.

    Google Scholar 

  16. Holoshitz J, Ling S . Nitric oxide signaling triggered by the rheumatoid arthritis shared epitope: a new paradigm for MHC disease association? Ann NY Acad Sci 2007; 1110: 73–83.

    Google Scholar 

  17. Gourraud PA, Boyer JF, Barnetche T, Abbal M, Cambon-Thomsen A, Cantagrel A et al. A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for rheumatoid arthritis structural severity. Arthritis Rheum 2006; 54: 593–599.

    Google Scholar 

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

    Google Scholar 

  19. Ota M, Katsuyama Y, Kimura A, Tsuchiya K, Kondo M, Naruse T 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.

    Google Scholar 

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

    Google Scholar 

  21. Newton JL, Harney SM, Timms AE, Sims AM, Rockett K, Darke C et al. Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis. Arthritis Rheum 2004; 50: 2122–2129.

    Google Scholar 

  22. Lee HS, Lee AT, Criswell LA, Seldin MF, Amos CI, Carulli JP et al. Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus. Mol Med 2008; 14: 293–300.

    Google Scholar 

  23. Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 2007; 450: 887–892.

    Google Scholar 

  24. Yen JH, Moore BE, Nakajima T, Scholl D, Schaid DJ, Weyand CM et al. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med 2001; 193: 1159–1167.

    Google Scholar 

  25. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J med 2007; 357: 977–986.

    Google Scholar 

  26. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004; 75: 330–337.

    Google Scholar 

  27. Zhernakova A, Alizadeh BZ, Bevova M, van Leeuwen MA, Coenen MJ, Franke B et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet 2007; 81: 1284–1288.

    Google Scholar 

  28. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004; 36: 337–338.

    Google Scholar 

  29. Begovich AB, Caillier SJ, Alexander HC, Penko JM, Hauser SL, Barcellos LF et al. The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. Am J Hum Genet 2005; 76: 184–187.

    Google Scholar 

  30. Jawaheer D, Seldin MF, Amos CI, Chen WV, Shigeta R, Etzel C et al. Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. Arthritis Rheum 2003; 48: 906–916.

    Google Scholar 

  31. Gregersen PK, Lee HS, Batliwalla F, Begovich AB . PTPN22: setting thresholds for autoimmunity. Semin Immunol 2006; 18: 214–223.

    Google Scholar 

  32. Carlton VE, Hu X, Chokkalingam AP, Schrodi SJ, Brandon R, Alexander HC et al. PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. Am J Hum Genet 2005; 77: 567–581.

    Google Scholar 

  33. Mastana S, Gilmour A, Ghelani A, Smith H, Samanta A . Association of PTPN22 with rheumatoid arthritis among South Asians in the UK. J Rheumatol 2007; 34: 1984–1986.

    Google Scholar 

  34. Ikari K, Momohara S, Inoue E, Tomatsu T, Hara M, Yamanaka H et al. Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford) 2006; 45: 1345–1348.

    Google Scholar 

  35. Lee HS, Korman BD, Le JM, Kastner DA, Remmers E, Gregersen P et al. Lack of association of Caucasian rheumatoid arthritis susceptibility loci in a Korean population. Arthritis Rheum 2008 (in press).

  36. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J Clin Endocrinol Metab 2004; 89: 5862–5865.

    Google Scholar 

  37. Skorka A, Bednarczuk T, Bar-Andziak E, Nauman J, Ploski R . Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves' disease in a Polish population: association and gene dose-dependent correlation with age of onset. Clin Endocrinol (Oxf) 2005; 62: 679–682.

    Google Scholar 

  38. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53: 3020–3023.

    Google Scholar 

  39. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 2005; 76: 561–571.

    Google Scholar 

  40. Vandiedonck C, Capdevielle C, Giraud M, Krumeich S, Jais JP, Eymard B et al. Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis. Ann Neurol 2006; 59: 404–407.

    Google Scholar 

  41. Dieude P, Guedj M, Wipff J, Avouac J, Hachulla E, Diot E et al. The PTPN22 620W allele confers susceptibility to systemic sclerosis: findings of a large case–control study of European Caucasians and a meta-analysis. Arthritis Rheum 2008; 58: 2183–2188.

    Google Scholar 

  42. LaBerge GS, Bennett DC, Fain PR, Spritz RA . PTPN22 is genetically associated with risk of generalized vitiligo, but CTLA4 is not. J Invest Dermatol 2008; 128: 1757–1762.

    Google Scholar 

  43. Skinningsrud B, Husebye ES, Gervin K, Lovas K, Blomhoff A, Wolff AB et al. Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. Eur J Hum Genet 2008; 16: 977–982.

    Google Scholar 

  44. Betz RC, Konig K, Flaquer A, Redler S, Eigelshoven S, Kortum AK et al. The R620W polymorphism in PTPN22 confers general susceptibility for the development of alopecia areata. Br J dermatol 2008; 158: 389–391.

    Google Scholar 

  45. Hinks A, Barton A, John S, Bruce I, Hawkins C, Griffiths CE et al. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum 2005; 52: 1694–1699.

    Google Scholar 

  46. Viken MK, Amundsen SS, Kvien TK, Boberg KM, Gilboe IM, Lilleby V et al. Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases. Genes immun 2005; 6: 271–273.

    Google Scholar 

  47. Seldin MF, Shigeta R, Laiho K, Li H, Saila H, Savolainen A et al. Finnish case–control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis. Genes immun 2005; 6: 720–722.

    Google Scholar 

  48. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008; 40: 204–210.

    Google Scholar 

  49. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J med 2008; 358: 900–909.

    Google Scholar 

  50. De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A et al. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. Eur J Hum Genet 2006; 14: 317–321.

    Google Scholar 

  51. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008; 40: 955–962.

    Google Scholar 

  52. Hasegawa K, Martin F, Huang G, Tumas D, Diehl L, Chan AC . PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 2004; 303: 685–689.

    Google Scholar 

  53. Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattari P et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 2005; 37: 1317–1319.

    Google Scholar 

  54. Rieck M, Arechiga A, Onengut-Gumuscu S, Greenbaum C, Concannon P, Buckner JH . Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J Immunol 2007; 179: 4704–4710.

    Google Scholar 

  55. Vang T, Miletic AV, Arimura Y, Tautz L, Rickert RC, Mustelin T . Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol 2008; 26: 29–55.

    Google Scholar 

  56. Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q et al. A biosynthetic pathway for anandamide. Proc Natl Acad Sci USA 2006; 103: 13345–13350.

    Google Scholar 

  57. Price AL, Butler J, Patterson N, Capelli C, Pascali VL, Scarnicci F et al. Discerning the ancestry of European Americans in genetic association studies. PLoS Genet 2008; 4: e236.

    Google Scholar 

  58. Tian C, Plenge RM, Ransom M, Lee A, Villoslada P, Selmi C et al. Analysis and application of European genetic substructure using 300K SNP information. PLoS Genet 2008; 4: e4.

    Google Scholar 

  59. Seldin MF, Price AL . Application of ancestry informative markers to association studies in European Americans. PLoS Genet 2008; 4: e5.

    Google Scholar 

  60. Kurreeman FA, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, Stoeken-Rijsbergen G et al. A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med 2007; 4: e278.

    Google Scholar 

  61. Barton A, Thomson W, Ke X, Eyre S, Hinks A, Bowes J et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17: 2274–2279.

    Google Scholar 

  62. Ravetch JV, Clynes RA . Divergent roles for Fc receptors and complement in vivo. Annu Rev Immunol 1998; 16: 421–432.

    Google Scholar 

  63. Wang Y, Rollins SA, Madri JA, Matis LA . Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc Natl Acad Sci USA 1995; 92: 8955–8959.

    Google Scholar 

  64. Wang Y, Kristan J, Hao L, Lenkoski CS, Shen Y, Matis LA . A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. J Immunol 2000; 164: 4340–4347.

    Google Scholar 

  65. Ward PA, Zvaifler NJ . Complement-derived leukotactic factors in inflammatory synovial fluids of humans. J Clin Invest 1971; 50: 606–616.

    Google Scholar 

  66. Gulati P, Guc D, Lemercier C, Lappin D, Whaley K . Expression of the components and regulatory proteins of the classical pathway of complement in normal and diseased synovium. Rheumatol Int 1994; 14: 13–19.

    Google Scholar 

  67. Neumann E, Barnum SR, Tarner IH, Echols J, Fleck M, Judex M et al. Local production of complement proteins in rheumatoid arthritis synovium. Arthritis Rheum 2002; 46: 934–945.

    Google Scholar 

  68. Vergunst CE, Gerlag DM, Dinant H, Schulz L, Vinkenoog M, Smeets TJ et al. Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation. Rheumatology (Oxford) 2007; 46: 1773–1778.

    Google Scholar 

  69. Arch RH, Gedrich RW, Thompson CB . Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death. Genes dev 1998; 12: 2821–2830.

    Google Scholar 

  70. Speiser DE, Lee SY, Wong B, Arron J, Santana A, Kong YY et al. A regulatory role for TRAF1 in antigen-induced apoptosis of T cells. J Exp Med 1997; 185: 1777–1783.

    Google Scholar 

  71. Tsitsikov EN, Laouini D, Dunn IF, Sannikova TY, Davidson L, Alt FW et al. TRAF1 is a negative regulator of TNF signaling. Enhanced TNF signaling in TRAF1-deficient mice. Immunity 2001; 15: 647–657.

    Google Scholar 

  72. Bishop GA . The multifaceted roles of TRAFs in the regulation of B-cell function. Nat Rev Immunol 2004; 4: 775–786.

    Google Scholar 

  73. Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 2008; 40: 1216–1223.

    Google Scholar 

  74. Wang S, Robertson GP, Zhu J . A novel human homologue of Drosophila polycomb-like gene is up-regulated in multiple cancers. Gene 2004; 343: 69–78.

    Google Scholar 

  75. Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK . Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med 2007; 13: 455–460.

    Google Scholar 

  76. Kobayashi S, Ikari K, Kaneko H, Kochi Y, Yamamoto K, Shimane K et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008; 58: 1940–1946.

    Google Scholar 

  77. Korman BD, Alba MI, Le JM, Alevizos I, Smith JA, Nikolov NP et al. Variant form of STAT4 is associated with primary Sjogren's syndrome. Genes immun 2008; 9: 267–270.

    Google Scholar 

  78. Levy DE, Darnell Jr JE . Stats: transcriptional control and biological impact. Nat Rev 2002; 3: 651–662.

    Google Scholar 

  79. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell Jr JE et al. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med 1995; 181: 1755–1762.

    Google Scholar 

  80. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ . Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 2004; 202: 139–156.

    Google Scholar 

  81. Kaplan MH, Sun YL, Hoey T, Grusby MJ . Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 1996; 382: 174–177.

    Google Scholar 

  82. Hildner KM, Schirmacher P, Atreya I, Dittmayer M, Bartsch B, Galle PR et al. Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. J Immunol 2007; 178: 3427–3436.

    Google Scholar 

  83. Yap WH, Yeoh E, Tay A, Brenner S, Venkatesh B . STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells. FEBS Lett 2005; 579: 4470–4478.

    Google Scholar 

  84. Fukao T, Frucht DM, Yap G, Gadina M, O′Shea JJ, Koyasu S . Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J Immunol 2001; 166: 4446–4455.

    Google Scholar 

  85. Remoli ME, Ragimbeau J, Giacomini E, Gafa V, Severa M, Lande R et al. NF-{kappa}B is required for STAT-4 expression during dendritic cell maturation. J Leukoc Biol 2007; 81: 355–363.

    Google Scholar 

  86. Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O et al. A common STAT4 risk haplotype for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA production and shows additive effects with two IRF5 risk alleles. Hum Mol Genet 2008; 17: 2868–2876.

    Google Scholar 

  87. Kuroda E, Kito T, Yamashita U . Reduced expression of STAT4 and IFN-gamma in macrophages from BALB/c mice. J Immunol 2002; 168: 5477–5482.

    Google Scholar 

  88. Walker JG, Ahern MJ, Coleman M, Weedon H, Papangelis V, Beroukas D et al. Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis. Ann Rheum Dis 2006; 65: 149–156.

    Google Scholar 

  89. Walker JG, Ahern MJ, Coleman M, Weedon H, Papangelis V, Beroukas D et al. Changes in synovial tissue Jak-STAT expression in rheumatoid arthritis in response to successful DMARD treatment. Ann Rheum Dis 2006; 65: 1558–1564.

    Google Scholar 

  90. Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007; 39: 1477–1482.

    Google Scholar 

  91. Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J et al. Rheumatoid arthritis association at 6q23. Nat Genet 2007; 39: 1431–1433.

    Google Scholar 

  92. Muller T, Anlag K, Wildner H, Britsch S, Treier M, Birchmeier C . The bHLH factor olig3 coordinates the specification of dorsal neurons in the spinal cord. Genes Dev 2005; 19: 733–743.

    Google Scholar 

  93. Ding L, Takebayashi H, Watanabe K, Ohtsuki T, Tanaka KF, Nabeshima Y et al. Short-term lineage analysis of dorsally derived Olig3 cells in the developing spinal cord. Dev Dyn 2005; 234: 622–632.

    Google Scholar 

  94. Wertz IE, O′Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004; 430: 694–699.

    Google Scholar 

  95. Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 2004; 5: 1052–1060.

    Google Scholar 

  96. Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE et al. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 2008; 28: 381–390.

    Google Scholar 

  97. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000; 289: 2350–2354.

    Google Scholar 

  98. Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet 2008; 40: 1062–1064.

    Google Scholar 

  99. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003; 34: 395–402.

    Google Scholar 

  100. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 2005; 77: 1044–1060.

    Google Scholar 

  101. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003; 34: 395–402.

    Google Scholar 

  102. Chang X, Yamada R, Suzuki A, Sawada T, Yoshino S, Tokuhiro S et al. Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 2005; 44: 40–50.

    Google Scholar 

  103. Hung HC, Lin CY, Liao YF, Hsu PC, Tsay GJ, Liu GY . The functional haplotype of peptidylarginine deiminase IV (S55G, A82 V and A112G) associated with susceptibility to rheumatoid arthritis dominates apoptosis of acute T leukemia Jurkat cells. Apoptosis 2007; 12: 475–487.

    Google Scholar 

  104. Cha S, Choi CB, Han TU, Kang CP, Kang C, Bae SC . Association of anti-cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis. Arthritis Rheum 2007; 56: 1454–1463.

    Google Scholar 

  105. Klareskog L, Padyukov L, Ronnelid J, Alfredsson L . Genes, environment and immunity in the development of rheumatoid arthritis. Curr Opin Immunol 2006; 18: 650–655.

    Google Scholar 

  106. Costenbader KH, Chang SC, De Vivo I, Plenge R, Karlson EW . Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking. Arthritis Res Ther 2008; 10: R52.

    Google Scholar 

  107. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39: 857–864.

    Google Scholar 

  108. van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 2007; 39: 827–829.

    Google Scholar 

  109. Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease Loci. PLoS Genet 2008; 4: e1000041.

    Google Scholar 

  110. Schumacher JM, Lee K, Edelhoff S, Braun RE . Distribution of Tenr, an RNA-binding protein, in a lattice-like network within the spermatid nucleus in the mouse. Biol Reprod 1995; 52: 1274–1283.

    Google Scholar 

  111. Leonard WJ, Spolski R . Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol 2005; 5: 688–698.

    Google Scholar 

  112. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 2008; 454: 350–352.

    Google Scholar 

  113. Li J, Shen W, Kong K, Liu Z . Interleukin-21 induces T-cell activation and proinflammatory cytokine secretion in rheumatoid arthritis. Scand J Immunol 2006; 64: 515–522.

    Google Scholar 

  114. Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 2007; 56: 1152–1163.

    Google Scholar 

  115. Malek TR . The biology of interleukin-2. Annu Rev Immunol 2008; 26: 453–479.

    Google Scholar 

  116. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 2007; 39: 1065–1067.

    Google Scholar 

  117. Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 2007; 80: 1037–1054.

    Google Scholar 

  118. Fellermann K, Stange DE, Schaeffeler E, Schmalzl H, Wehkamp J, Bevins CL et al. A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hum Genet 2006; 79: 439–448.

    Google Scholar 

  119. Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005; 307: 1434–1440.

    Google Scholar 

  120. Burns JC, Shimizu C, Gonzalez E, Kulkarni H, Patel S, Shike H et al. Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease. J Infect Dis 2005; 192: 344–349.

    Google Scholar 

  121. McKinney C, Merriman ME, Chapman PT, Gow PJ, Harrison AA, Highton J et al. Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis. Ann Rheum Dis 2008; 67: 409–413.

    Google Scholar 

  122. Liu C, Batliwalla F, Li W, Lee A, Roubenoff R, Beckman E et al. Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med 2008; 14: 575–581.

    Google Scholar 

Download references

Acknowledgements

MC is supported by a grant from the Netherlands Organization for Scientific Research (Grant 916.76.020). PKG is supported by grants from the NIH (RO1 AR44422, RO1-AI-68759, NO1-AR-2-2263, NO1-AR-1-2256), the American College of Rheumatology, the Eileen Ludwig Greenland Fund and The Muriel Fusfeld Foundation.

Author information

Authors and Affiliations

  1. Department of Human Genetics of the Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    M J H Coenen

  2. The Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA

    P K Gregersen

Authors
  1. M J H Coenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P K Gregersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P K Gregersen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coenen, M., Gregersen, P. Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun 10, 101–111 (2009). https://doi.org/10.1038/gene.2008.77

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2008.77

Keywords

This article is cited by

Search

Advanced search

Quick links