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Rheumatoid arthritis genetics: 2009 update

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Abstract

Recent human genetic discoveries have increased our understanding of rheumatoid arthritis (RA) susceptibility. Genome-wide association studies have expanded the number of validated RA risk loci beyond HLA-DRB1 “shared epitope” alleles to include additional major histocompatibility complex (MHC) risk alleles and more than 10 regions outside the MHC. The newly discovered risk alleles are common in the general population, have a modest effect on RA risk, and together explain less than 5% of the variance in disease risk. Whereas the actual causal mutation and causal gene for most loci remain to be determined, these studies are beginning to reveal general themes: many risk loci are associated with other autoimmune diseases; many genes fall within discrete biological pathways (eg, the nuclear factor κ-light-chain-enhancer of activated B cells signaling pathway); and human genetics can group diseases into clinically meaningful subset categories (eg, presence or absence of autoantibodies). This review discusses recent RA genetic discoveries in terms of their potential to improve patient care.

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References and Recommended Reading

  1. Lander ES, Linton LM, Birren B, et al.: Initial sequencing and analysis of the human genome. Nature 2001, 409:860–921.

    Article  PubMed  CAS  Google Scholar 

  2. Consortium IH, Frazer KA, Ballinger DG, et al.: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007, 449:851–861.

    Article  CAS  Google Scholar 

  3. Altshuler D, Daly MJ, Lander ES: Genetic mapping in human disease. Science 2008, 322:881–888.

    Article  PubMed  CAS  Google Scholar 

  4. Firestein GS: Evolving concepts of rheumatoid arthritis. Nature 2003, 423:356–361.

    Article  PubMed  CAS  Google Scholar 

  5. Consortium TIHM: A haplotype map of the human genome. Nature 2005, 437:1299–1320.

    Article  CAS  Google Scholar 

  6. Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005, 6:95–108.

    Article  PubMed  CAS  Google Scholar 

  7. Purcell S, Neale B, Todd-Brown K, et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81:559–575.

    Article  PubMed  CAS  Google Scholar 

  8. Price AL, Patterson NJ, Plenge RM, et al.: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006, 38:904–909.

    Article  PubMed  CAS  Google Scholar 

  9. Marchini J, Howie B, Myers S, et al.: A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 2007, 39:906–913.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  11. Gregersen PK, Moriuchi T, Karr RW, et al.: Polymorphism of HLA-DR beta chains in DR4, −7, and −9 haplotypes: implications for the mechanisms of allelic variation. Proc Natl Acad Sci U S A 1986, 83:9149–9153.

    Article  PubMed  CAS  Google Scholar 

  12. Gregersen PK, Shen M, Song QL, et al.: Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci U S A 1986, 83:2642–2646.

    Article  PubMed  CAS  Google Scholar 

  13. 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  PubMed  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. 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  PubMed  CAS  Google Scholar 

  16. 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.

    PubMed  CAS  Google Scholar 

  17. Kochi Y, Yamada R, Kobayashi K, et al.: Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences. Arthritis Rheum 2004, 50:63–71.

    Article  PubMed  CAS  Google Scholar 

  18. Lee HS, Lee AT, Criswell LA, 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.

    Article  PubMed  Google Scholar 

  19. Vignal C, Bansal AT, Balding DJ, et al.: Genetic association of the major histocompatibility complex with rheumatoid arthritis implicates two non-DRB1 loci. Arthritis Rheum 2008, 60:53–62.

    Article  CAS  Google Scholar 

  20. Ding B, Padyukov L, Lundstrom E, et al.: Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region. Arthritis Rheum 2008, 60:30–38.

    Article  CAS  Google Scholar 

  21. Begovich AB, Carlton VE, Honigberg LA, 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.

    Article  PubMed  CAS  Google Scholar 

  22. Remmers EF, Plenge RM, Lee AT, et al.: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007, 357:977–986.

    Article  PubMed  CAS  Google Scholar 

  23. Plenge RM, Seielstad M, Padyukov L, et al.: TRAF1-C5 as a risk locus for rheumatoid arthritis—a Genomewide Study. N Engl J Med 2007, 357:1199–1209.

    Article  PubMed  CAS  Google Scholar 

  24. Kurreeman FA, Padyukov L, Marques RB, et al.: A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med 2007, 4:e278.

    Article  PubMed  CAS  Google Scholar 

  25. Plenge RM, Cotsapas C, Davies L, et al.: Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007, 39:1477–1482.

    Article  PubMed  CAS  Google Scholar 

  26. Thomson W, Barton A, Ke X, et al.: Rheumatoid arthritis association at 6q23. Nat Genet 2007, 39:1431–1433.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Plenge RM, Padyukov L, Remmers EF, 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.

    Article  PubMed  CAS  Google Scholar 

  29. Chang M, Rowland CM, Garcia VE, et al.: A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2. PLoS Genet 2008, 4:e1000107.

  30. Zhernakova A, Alizadeh BZ, Bevova M, 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.

    Article  PubMed  CAS  Google Scholar 

  31. Consortium WTCC: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447:661–678.

    Article  CAS  Google Scholar 

  32. Barton A, Thomson W, Ke X, 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, 68:1373–1375.

    Google Scholar 

  33. Barton A, Thomson W, Ke X, et al.: Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat Genet 2008, 40:1156–1159.

    Article  PubMed  CAS  Google Scholar 

  34. Raychaudhuri S, Remmers EF, Lee AT, et al.: Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 2008, 40:1216–1223.

    Article  PubMed  CAS  Google Scholar 

  35. Suzuki A, Yamada R, Kochi Y, et al.: Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nat Genet 2008, 40:1224–1229.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  37. 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  PubMed  CAS  Google Scholar 

  38. Cornelis F, Faure S, Martinez M, et al.: New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci U S A 1998, 95:10746–10750.

    Article  PubMed  CAS  Google Scholar 

  39. Jawaheer D, Seldin MF, Amos CI, et al.: A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet 2001, 68:927–936.

    Article  PubMed  CAS  Google Scholar 

  40. Jacobson EM, Concepcion E, Oashi T, Tomer Y: A Graves’ disease-associated Kozak sequence single-nucleotide polymorphism enhances the efficiency of CD40 gene translation: a case for translational pathophysiology. Endocrinology 2005, 146:2684–2691.

    Article  PubMed  CAS  Google Scholar 

  41. Plenge RM: Shared genetic risk factors for type 1 diabetes and celiac disease. N Engl J Med 2008, 359:2837–2838.

    Article  PubMed  CAS  Google Scholar 

  42. Smyth DJ, Plagnol V, Walker NM, et al.: Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 2008, 359:2767–2777.

    Article  PubMed  CAS  Google Scholar 

  43. International Multiple Sclerosis Genetics Consortium (IMSGC): The expanding genetic overlap between multiple sclerosis and type I diabetes. Genes Immun 2009, 10:11–14.

    Article  CAS  Google Scholar 

  44. Behrens EM, Finkel TH, Bradfield JP, et al.: Association of the TRAF1-C5 locus on chromosome 9 with juvenile idiopathic arthritis. Arthritis Rheum 2008, 58:2206–2207.

    Article  PubMed  Google Scholar 

  45. Fung E, Smyth DJ, Howson JM, et al.: Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 2008, 10:188–191.

    Article  PubMed  CAS  Google Scholar 

  46. Graham RR, Cotsapas C, Davies L, et al.: Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 2008, 40:1059–1061.

    Article  PubMed  CAS  Google Scholar 

  47. Musone SL, Taylor KE, Lu TT, et al.: Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet 2008, 40:1062–1064.

    Article  PubMed  CAS  Google Scholar 

  48. Barrett JC, Hansoul S, Nicolae DL, et al.: Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008, 40:955–962.

    Article  PubMed  CAS  Google Scholar 

  49. van der Helm-van Mil AH, Huizinga TW: Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets. Arthritis Res Ther 2008, 10:205.

    Article  PubMed  CAS  Google Scholar 

  50. Huizinga TW, Amos CI, van der Helm-van Mil AH, et al.: Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum 2005, 52:3433–3438.

    Article  PubMed  CAS  Google Scholar 

  51. Irigoyen P, Lee AT, Wener MH, 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.

    Article  PubMed  CAS  Google Scholar 

  52. Lee AT, Li W, Liew A, et al.: The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status. Genes Immun 2005, 6:129–133.

    Article  PubMed  CAS  Google Scholar 

  53. Takata Y, Inoue H, Sato A, et al.: Replication of reported genetic associations of PADI4, FCRL3, SLC22A4 and RUNX1 genes with rheumatoid arthritis: results of an independent Japanese population and evidence from meta-analysis of East Asian studies. J Hum Genet 2008, 53:163–173.

    Article  PubMed  CAS  Google Scholar 

  54. Barton A, Bowes J, Eyre S, et al.: A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 2004, 50:1117–1121.

    Article  PubMed  CAS  Google Scholar 

  55. Martinez A, Valdivia A, Pascual-Salcedo D, et al.: PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology (Oxford) 2005, 44:1263–1266.

    Article  CAS  Google Scholar 

  56. Poor G, Nagy ZB, Schmidt Z, et al.: Genetic background of anticyclic citrullinated peptide autoantibody production in Hungarian patients with rheumatoid arthritis. Ann N Y Acad Sci 2007, 1110:23–32.

    Article  PubMed  CAS  Google Scholar 

  57. Ikari K, Momohara S, Inoue E, et al.: Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford) 2006, 45:1345–1348.

    Article  CAS  Google Scholar 

  58. Lee EG, Boone DL, Chai S, et al.: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000, 289:2350–2354.

    Article  PubMed  CAS  Google Scholar 

  59. van der Helm-van Mil AH, Detert J, le Cessie S, et al.: Validation of a prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: moving toward individualized treatment decision-making. Arthritis Rheum 2008, 58:2241–2247.

    Article  PubMed  Google Scholar 

  60. van der Helm-van Mil AH, le Cessie S, van Dongen H, et al.: A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum 2007, 56:433–440.

    Article  PubMed  Google Scholar 

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  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Suite 168, Boston, MA, 02115, USA

    Robert M. Plenge

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  1. Robert M. Plenge
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Plenge, R.M. Rheumatoid arthritis genetics: 2009 update. Curr Rheumatol Rep 11, 351–356 (2009). https://doi.org/10.1007/s11926-009-0050-0

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