Journal of Genetics

, Volume 93, Issue 2, pp 597–605

Association of susceptible genetic markers and autoantibodies in rheumatoid arthritis



Rheumatoid arthritis (RA) is a chronic autoimmune disorder of unknown aetiology resulting in inflammation of the synovium, cartilage and bone. The disease has a heterogeneous character, consisting of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although, the pathogenesis of RA is incompletely understood, genetic factors play a vital role in susceptibility to RA as the heritability of RA is between 50 and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. Non-HLA genes, i.e. tumour necrosis factor-α (TNF- α) within the MHC (major histocompatibility complex) have also been investigated for association with RA. Although, some contradictory results have originated from several studies on TNF-α gene, the data published so far indicate the possible existence of TNF-α gene promoter variants that act as markers for disease severity and response to treatment in RA. The correlation of HLA and non-HLA genes within MHC region is apparently interpreted. A considerable number of confirmed associations with RA and other autoimmune disease susceptibility loci including peptidylarginine deiminase type 4 (PADI4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), signal transducer and activator of transcription (STAT4), cluster of differentiation 244 (CD244) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), located outside the MHC have been reported recently. In this review, we aim to give an update on recent progress in RA genetics, the importance of the combination of HLA-DRB1 alleles, non-HLA gene polymorphism, its detection and autoantibodies as susceptibility markers for early RA disease.


allele anti-CCP MHC shared epitope SNP. 


  1. Aho K., Koskenvuo M., Tuominen J. and Kaprio J. 1986 Occurrence of rheumatoid arthritis in a nationwide series of twins. J. Rheumatol. 13, 899–902.PubMedGoogle Scholar
  2. Arch R. H., Gedrich R. W. and Thompson C. B. 1998 Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death. Genes Dev. 12, 2821–2830.PubMedCrossRefGoogle Scholar
  3. Auger I., Sebbag M., Vincent C., Balandraud N., Guis S., Nogueira L., et al. 2005 Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum. 52, 3424–3432.PubMedCrossRefGoogle Scholar
  4. Bas S., Perneger T. V., Kunzle E. and Vischer L. 2002 Comparative study of different enzyme immunoassays for measurement of IgM and IgA rheumatoid factors. Ann. Rheum. Dis. 61, 505–510.PubMedCentralPubMedCrossRefGoogle Scholar
  5. Begovich A. B., Carlton V. E., Honigberg L. A., Schrodi S. J., Chokkalingam A. P., Alexander H. C. et al. 2004 A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337.PubMedCentralPubMedCrossRefGoogle Scholar
  6. Berglin E., Padyukov L., Sundin U., Hallmans G., Stenlund H., Van Venrooij W. J., et al. 2004 A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res. Ther. 6, R303–R308.PubMedCentralPubMedCrossRefGoogle Scholar
  7. Bhayani H. R. and Hedrick S. M. 1991 The role of polymorphic amino acids of the MHC molecule in the selection of the T cell repertoire. J. Immunol. 146, 1093–1098.PubMedGoogle Scholar
  8. Bizzaro N., Mazzanti G., Tonutti E., Villalta D. and Tozzoli R. 2001 Diagnostic accuracy of the anti-citrulline antibody assay for rheumatoid arthritis. Clin. Chem. 47, 1089–1093.PubMedGoogle Scholar
  9. Bowes J. and Barton A. 2008 Recent advances in the genetics of RA susceptibility. Rheumatology (Oxford) 47, 399–402.CrossRefGoogle Scholar
  10. Brinkman B. M., Kaijzel E. L., Huizinga T. W., Giphart M. J., Breedveld F. C and Verweij C. L. 1995 Detection of a novel c-insertion polymorphism within the human tumor necrosis factor alpha gene. Hum. Genet. 96, 493.PubMedCrossRefGoogle Scholar
  11. Caponi L., Petit-Teixeira E., Sebbag M., Bongiorni F., Moscato S., Pratesi F., et al. 2005 A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann. Rheum. Dis. 64, 587–593.PubMedCentralPubMedCrossRefGoogle Scholar
  12. Carlton V. E., Hu X., Chokkalingam A. P., Schrodi S. J., Brandon R., Alexander H. C., et al. 2005 PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. Am. J. Hum. Genet. 77, 567–581.PubMedCentralPubMedCrossRefGoogle Scholar
  13. Chang X., Xia Y., Pan J., Meng Q., Zhao Y., et al. 2013 PADI2 is significantly associated with rheumatoid arthritis. PLoS One 8, e81259.PubMedCentralPubMedCrossRefGoogle Scholar
  14. Cho S. K., Han T. U., Kim K., Bang S. Y., Bae S. C. and Kang C. 2009 CD244 is not associated with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in a Korean population. Arthritis Rheum. 60, 3153–3154.PubMedCrossRefGoogle Scholar
  15. Coenen M. J. and Gregersen P. K. 2009 Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun. 10, 101–111.PubMedCentralPubMedCrossRefGoogle Scholar
  16. Daha N. A., Kurreeman F. A., Marques R. B., Stoeken-Rijsbergen G., Verduijn W., Huizinga T. W., et al. 2009 Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum. 60, 1255–1260.PubMedCrossRefGoogle Scholar
  17. Danis V. A, Millington M., Hyland V., Lawford R., Huang Q. and Grennan D. 1995 Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Dis. Markers 12, 127–133.PubMedCrossRefGoogle Scholar
  18. Ding B., Padyukov L., Lundström E., Seielstad M., Plenge R. M., Oksenberg J. R., et al. 2009 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. 60, 30–38.PubMedCentralPubMedCrossRefGoogle Scholar
  19. Field M., Gallagher G., Eskdale J., McGarry F., Richards S. D., Munro R., et al. 1997 Tumor necrosis factor locus polymorphisms in rheumatoid arthritis. Tissue Antigens 50, 303–307.PubMedCrossRefGoogle Scholar
  20. Firestein G. S. 1997 Etiology and pathogenesis of rheumatoid arthritis: Textbook of rheumatology, 5th edition, p. 851–897, W. B. Saunders, Philadelphia.Google Scholar
  21. Gregersen P. K. 2005 Gaining insight into PTPN22 and autoimmunity. Nat. Genet. 37, 1300–1302.PubMedCrossRefGoogle Scholar
  22. Gregersen P. K., Silver J. and Winchester R. J. 1987 The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213.PubMedCrossRefGoogle Scholar
  23. Hill R. J., Zozulya S., Lu Y. L., Ward K., Gishizky M. and Jallal B. 2002 The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp. Hematol. 30, 237–244.PubMedCrossRefGoogle Scholar
  24. Hill J. A., Southwood S., Sette A., Jevnikar A. M., Bell D. A. and Cairns E. 2003 Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLADRB1*0401 MHC class II molecule. J. Immunol. 171, 538–541.PubMedCrossRefGoogle Scholar
  25. Holoshitz J. and Ling S. 2007 Nitric oxide signaling triggered by the rheumatoid arthritis shared epitope: a new paradigm for MHC-disease association. Ann. New York Acad. Sci. 1110, 73–83.CrossRefGoogle Scholar
  26. Huizinga T. W., Amos C. I., van der Helm-van Mil A. H., Chen W., van Gaalen F. A., Jawaheer D., et al. 2005 Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 52, 3433–3438.PubMedCrossRefGoogle Scholar
  27. Irigoyen P., Lee A. T., Wener M. H., Li W., Kern M., Batliwalla F., et al. 2005 Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum. 52, 3813–3818.PubMedCrossRefGoogle Scholar
  28. Julià A., Ballina J., Canete J. D., Balsa A., Tornero-Molina J., Naranjo A., et al. 2008 Genome-wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility. Arthritis Rheum. 58, 2275–2286.PubMedCrossRefGoogle Scholar
  29. Kang C. P., Lee H. S., Ju H., Cho H., Kang C. and Bae S. C. 2006 A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum. 54, 90–96.PubMedCrossRefGoogle Scholar
  30. Kochi Y., Suzuki A., Yamada R. and Yamamoto K. 2009 Genetics of rheumatoid arthritis: underlying evidence of ethnic differences. J. Autoimmun. 32, 158–162.PubMedCrossRefGoogle Scholar
  31. Kurreeman F. A., Padyukov L., Marques R. B., Schrodi S. J., Seddighzadeh M., Stoeken-Rijsbergen G., et al. 2007 A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med. 4, e278.PubMedCentralPubMedCrossRefGoogle Scholar
  32. Lamana A., Balsa A., Rueda B., Ortiz A. M., Nuno L., Miranda-Carus M. E. et al. 2012 The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis. PLoS One 7, e43661.PubMedCentralPubMedCrossRefGoogle Scholar
  33. Lawrence J. S. 1969 The epidemiology and genetics of rheumatoid arthritis. Rheumatology 2, 1–36.PubMedGoogle Scholar
  34. Lee C. S., Lee Y. J, Liu H. F., Su C. H., Chang S. C., Wang B. R. et al. 2003 Association of CTLA4 gene A-G polymorphism with rheumatoid arthritis in Chinese. Clin. Rheumatol. 22, 221–224.PubMedCrossRefGoogle Scholar
  35. Lee Y. H., Woo J. H., Choi S. J., Ji J. D. and Song G. G. 2010 Association between the rs7574865 polymorphism of STAT4 and rheumatoid arthritis: a metaanalysis. Rheumatol. Int. 30, 661–666.PubMedCrossRefGoogle Scholar
  36. Legrand L., Lathrop G. M., Marcelli-Barge A., Dryll A., Bardin T., Debeyre N. et al. 1984 HLA-DR genotype risks in seropositive rheumatoid arthritis. Am. J. Hum. Genet. 36, 690–699.PubMedCentralPubMedGoogle Scholar
  37. Low A. S., Gonzalez-Gay M. A., Akil M., Amos R. S., Bax D. E., Cannings C. et al. 2002 TNF +489 polymorphism does not contribute to susceptibility to rheumatoid arthritis. Clin. Exp. Rheumatol. 20, 829–832.PubMedGoogle Scholar
  38. MacGregor A. J., Snieder H., Rigby A. S., Koskenvuo M., Kaprio J., Aho K. et al. 2000 Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 43, 30–37.PubMedCrossRefGoogle Scholar
  39. Martinez A., Valdivia A., Pascual-Salcedo D., Lamas J. R., Fernández-Arquero M., Balsa A. et al. 2005 PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology 44, 1263–1266.PubMedCrossRefGoogle Scholar
  40. Matsuda M., Sakamoto N. and Fukumaki Y. 1992 Delta-thalassemia caused by disruption of the site for an erythroid-specific transcription factor, GATA-1, in the delta-globin gene promoter. Blood 80, 1347–1351.PubMedGoogle Scholar
  41. Michou L., Teixeira V. H., Pierlot C., Lasbleiz S., Bardin T., Dieudé P. et al. 2008 Associations between genetic factors, tobacco smoking and autoantibodies in familial and sporadic rheumatoid arthritis. Ann. Rheum. Dis. 67, 466–470.PubMedCrossRefGoogle Scholar
  42. Migita K., Nakamura T., Maeda Y., Miyashita T., Origuchi T., Yatsuhashi H. et al. 2006 HLA-DRB1*04 alleles in Japanese rheumatoid arthritis patients with AA amyloidosis. J. Rheumatol. 33, 2120–2123.PubMedGoogle Scholar
  43. Mourad J. and Monem F. 2013 HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria. Rev. Bras. Reumatol. 53, 51–56.CrossRefGoogle Scholar
  44. Mulcahy B., Waldron-Lynch F., McDermott M. F., Adams C., Amos C. I., Zhu D. K. et al. 1996 Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am. J. Hum. Genet. 59, 676.PubMedCentralPubMedGoogle Scholar
  45. Naqi N., Ahmed T. A., Malik J. M., Ahmed M. and Bashir M. M. 2011 HLA DR β1 Alleles in Pakistani patients with rheumatoid arthritis. J. Coll. Physicians Surg. Pak. 21, 727–730.PubMedGoogle Scholar
  46. Nielen M. M., van Schaardenburg D., Reesink H. W., van de Stadt R. J., van der Horst-Bruinsma I. E., de Koning M. H. et al. 2004 Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386.PubMedCrossRefGoogle Scholar
  47. Ollier W. E., Kennedy L. J., Thomson W., Barnes A. N., Bell S. C. and Bennett D. 2001 Dog MHC alleles containing the human RA shared epitope confer susceptibility to canine rheumatoid arthritis. Immunogenetics 53, 669–673.PubMedCrossRefGoogle Scholar
  48. Orozco G., Alizadeh B. Z., Delgado-Vega A. M., González-Gay M. A, Balsa A., Pascual-Salcedo D. et al. 2008 Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum. 58, 1974–1980.PubMedCrossRefGoogle Scholar
  49. Padyukov L., Silva C., Stolt P., Alfredsson L. and Klareskog L. 2004 A gene environment interaction between smoking and shared epitope genes in HLADR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 50, 3085–3092.PubMedCrossRefGoogle Scholar
  50. Panati K., Pal S., Rao K. V. and Reddy V. D. 2012 Association of single nucleotide polymorphisms (SNPs)of PADI4 gene with rheumatoid arthritis (RA) in Indian population. Genes Genet. Syst. 87, 191–196.PubMedGoogle Scholar
  51. Panoulas V. F., Smith J. P., Nightingale P., and Kitas G. D. 2009 Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis. Arthritis Rheum. 60, 39–46.PubMedCrossRefGoogle Scholar
  52. Pedersen M., Jacobsen S., Klarlund M., Pedersen B. V., Wiik A., Wohlfahrt J. et al. 2006 Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res. Ther. 8, R133.PubMedCentralPubMedCrossRefGoogle Scholar
  53. Plant D., Flynn E., Mbarek H., Dieudé P., Cornelis F., Arlestig L. et al. 2010 Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers. Ann. Rheum. Dis. 69, 1548–1553.PubMedCentralPubMedCrossRefGoogle Scholar
  54. Plenge R. M., Padyukov L., Remmers E. F., Purcell S., Lee A. T., Karlson E. W. et al. 2005 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. 77, 1044–1060.PubMedCentralPubMedCrossRefGoogle Scholar
  55. Plenge R. M., Cotsapas C., Davies L., Price A. L, de Bakker P. I., Maller J. et al. 2007a Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482.CrossRefGoogle Scholar
  56. Plenge R. M., Seielstad M., Padyukov L., Lee A. T., Remmers E. F., Ding B. et al. 2007b TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N. Engl. J. Med. 357, 1199–1209.CrossRefGoogle Scholar
  57. Pradhan V. D., Dalvi H., Parsannavar D., Rajadhyaksha A., Patwardhan M. and Ghosh K. 2012 Study of PTPN22 1858C/T polymorphism in rheumatoid arthritis patients from Western India. Ind. J. Rheumatol. 7, 130–134.CrossRefGoogle Scholar
  58. Raychaudhuri S., Remmers E. F., Lee A. T, Hackett R., Guiducci C., Burtt N. P. et al. 2008 Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223.PubMedCentralPubMedCrossRefGoogle Scholar
  59. Remmers E. F., Plenge R. M., Lee A. T., Graham R. R., Hom G., Behrens T. W. et al. 2007 STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986.PubMedCentralPubMedCrossRefGoogle Scholar
  60. Rose H. M., Ragan C., Pearce E. and Lipman M. O. 1948 Differential agglutination of normal and sensitized sheep erythrocytes by sera of patients with rheumatoid arthritis. Proc. Soc. Exp. Biol. Med. 68, 1–6.PubMedCrossRefGoogle Scholar
  61. Saraux A., Berthelot J. M., Chales G., Le Henaff C., Mary J. Y., Thorel J. B. et al. 2002 Value of laboratory tests in early prediction of rheumatoid arthritis. Arthritis Rheum. 47, 155–165.PubMedCrossRefGoogle Scholar
  62. Schellekens G. A., Visser H, de Jong B. A., van den Hoogen F. H., Hazes J. M., Breedveld F. C. et al. 2000 The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 3, 155–163.CrossRefGoogle Scholar
  63. Silman A. J., MacGregor A. J., Thomson W., Holligan S., Carthy D., Farhan A. et al. 1993 Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br. J. Rheumatol. 32, 903–907.PubMedCrossRefGoogle Scholar
  64. Speiser D. E., Lee S. Y., Wong B., Arron J., Santana A., Kong Y. Y. et al. 1997 A regulatory role for TRAF1 in antigen-induced apoptosis of T cells. J. Exp. Med. 185, 1777–1783.PubMedCentralPubMedCrossRefGoogle Scholar
  65. Stahl E. A., Raychaudhuri S., Remmers E. F., Xie G., Eyre S., Thomson B. P. et al. 2010 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508.PubMedCentralPubMedCrossRefGoogle Scholar
  66. Suppiah V., O’Doherty C., Heggarty S., Patterson C. C., Rooney M. and Vandenbroeck K. 2006 The CTLA4 +49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland. Exp. Mol. Pathol. 80, 141–146.PubMedCrossRefGoogle Scholar
  67. Suzuki A., Yamada R., Chang X., Tokuhiro S., Sawada T., Suzuki M. et al. 2003 Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402.PubMedCrossRefGoogle Scholar
  68. Suzuki A., Yamada R., Kochi Y., Sawada T., Okada Y., Matsuda K. et al. 2008 Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nat. Genet. 40, 1224–1249.PubMedCrossRefGoogle Scholar
  69. Symmons D. P., Bankhead C. R., Harrison B. J., Brennan P., Barrett E. M., Scott D. G. et al. 1997 Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum. 40, 1955–1961.PubMedCrossRefGoogle Scholar
  70. Tait B. D., Drummond B. P., Varney M. D. and Harrison L. C. 1995 HLA-DRB1*0401 is associated with susceptibility to insulin-dependent diabetes mellitus independently of the DQB1 locus. Eur. J. Immunogenet. 22, 289–297.PubMedCrossRefGoogle Scholar
  71. Takata Y., Inoue H., Sato A., Tsugawa K., Miyatake K., Hamada D. et al. 2008 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. 53, 163–173.PubMedCrossRefGoogle Scholar
  72. Tuokko J., Nejentsev S., Luukkainen R., Toivanen A. and Ilonen J. 2001 HLA haplotype analysis in Finnish patients with rheumatoid arthritis. Arthritis Rheum. 44, 315–322.PubMedCrossRefGoogle Scholar
  73. van der Helm-van Mil A. H. and Huizinga T. W. 2008 Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets. Arthritis Res. Ther. 10, 205.PubMedCentralPubMedCrossRefGoogle Scholar
  74. van der Helm-van Mil A. H., Verpoort K. N., Breedveld F. C., Huizinga T. W., Toes R. E. and de Vries R. R. 2006 The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 54, 1117–1121.PubMedCrossRefGoogle Scholar
  75. van der Woude D., Houwing-Duistermaat J. J., Toes R. E., Huizinga T. W., Thomson W., Worthington J. et al. 2009 Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis. Arthritis Rheum. 60, 916–923.PubMedCrossRefGoogle Scholar
  76. van Krugten M. V., Huizinga T. W., Kaijzel E. L., Zanelli E., Drossaers-Bakker K. W., van de Linde P. et al. 1999 Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis. Genes Immun. 1, 91–96.PubMedCrossRefGoogle Scholar
  77. Vasanth K. M. and Nalini G. 2011 Usefulness of genetic markers in rheumatoid arthritis. Proceedings of the International Conference on Medical Genetics and Genomics ICMG-2011: December 12–14; Bharathidasan University, Tiruchirappalli, India.Google Scholar
  78. Veillette A. 2006 Immune regulation by SLAM family receptors and SAP-related adaptors. Nat. Rev. Immunol. 6, 56–66.PubMedCrossRefGoogle Scholar
  79. Verpoort K. N., van Gaalen F. A., van der Helm-van Mil A. H., Schreuder G. M., Breedveld F. C., Huizinga T. W. et al. 2005 Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum. 52, 3058–3062.PubMedCrossRefGoogle Scholar
  80. Vinasco J., Beraun Y., Nieto A., Fraile A., Mataran L., Pareja E. et al. 1997 Polymorphism at the TNF loci in rheumatoid arthritis. Tissue Antigens 49, 74–78.PubMedCrossRefGoogle Scholar
  81. Vossenaar E. R., Després N., Lapointe E., van der Heijden A., Lora M., Senshu T. et al. 2004 Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res. Ther. 6, R142–R150.PubMedCentralPubMedCrossRefGoogle Scholar
  82. Waldron-Lynch F., Adams C., Amos C., Zhu D. K., McDermott M. F., Shanahan F. et al. 2001 Tumour necrosis factor 5\(^{\prime }\) promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families. Genes Immun. 2, 82– 87.PubMedCrossRefGoogle Scholar
  83. Walker J. G. and Smith M. D. 2005 The Jak-STAT pathway in rheumatoid arthritis. J. Rheumatol. 32, 1650–1653.PubMedGoogle Scholar
  84. Watford W. T., Hissong B. D., Bream J. H., Kanno Y., Muul L. and O’Shea J. J. 2004 Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202, 139–156.PubMedCrossRefGoogle Scholar
  85. Weinblatt M. E. and Schur P. H. 1980 Rheumatoid factor detection by nephelometry. Arthritis Rheum. 23, 777–779.PubMedCrossRefGoogle Scholar
  86. Wellcome Trust Case Control Consortium 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678.CrossRefGoogle Scholar
  87. Wertz I. E., O’Rourke K. M., Zhou H., Eby M., Aravind L., Seshagiri S. et al. 2004 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430, 694–699.PubMedCrossRefGoogle Scholar
  88. Weyand C. M. and Goronzy J. 2000 Association of MHC and rheumatoid arthritis: HLA polymorphisms in phenotypic variants of rheumatoid arthritis. Arthritis Res. 2, 212–216.PubMedCentralPubMedCrossRefGoogle Scholar
  89. Weyand C. M, Hunder N. N., Hicok K. C., Hunder G. G. and Goronzy J. J. 1994 HLA-DRB1 alleles in polymyalgia rheumatica, giant cell arteritis, and rheumatoid arthritis. Arthritis Rheum. 37, 514–520.PubMedCrossRefGoogle Scholar
  90. Wilson A. G., de Vries N., Pociot F., di Giovine F. S., van der Putte L. B. and Duff G. W. 1993 An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles. J. Exp. Med. 177, 557–560.PubMedCrossRefGoogle Scholar
  91. Wilson A. G, de Vries N., van de Putte L. B. and Duff G. W. 1995 A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis. Ann. Rheum. Dis. 54, 601–603.PubMedCentralPubMedCrossRefGoogle Scholar
  92. Wucherpfennig K. W. and Strominger J. L. 1995 Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases. J. Exp. Med. 181, 1597–1601.PubMedCrossRefGoogle Scholar
  93. Yen J. H., Chen C. J., Tsai W. C., Lin C. H., Ou T. T, Wu C. C. et al. 2001 Tumor necrosis factor promoter polymorphisms in patients with rheumatoid arthritis in Taiwan. J. Rheumatol. 28, 1788–1792.PubMedGoogle Scholar
  94. Zervou M. I., Sidiropoulos P., Petraki E., Vazgiourakis V., Krasoudaki E., Raptopoulou A. et al. 2008 Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Hum. Immunol. 69, 567–571.PubMedCrossRefGoogle Scholar
  95. Zhernakova A., Eerligh P., Barrera P., Wesoly J. Z., Huizinga T. W., Roep B. O. et al. 2005 CTLA4 is differentially associated with autoimmune diseases in the Dutch population. Hum. Genet. 118, 58–66.PubMedCrossRefGoogle Scholar

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© Indian Academy of Sciences 2014

Authors and Affiliations

    • 1
    • 1
    • 2
  1. 1.Department of BiochemistrySri Ramachandra UniversityChennaiIndia
  2. 2.Sri Ramachandra HospitalSri Ramachandra UniversityChennaiIndia

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