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Lamana, Amalia; Balsa, Alejandro; Rueda, Blanca; Ortiz, Ana M.; Nuño, Laura; Miranda-Carus, Maria Eugenia; Gonzalez-Escribano, Maria F.; Lopez-Nevot, Miguel A.; Pascual-Salcedo, Dora; Martin, Javier; González-Álvaro, Isidoro (2012)
Publisher: Public Library of Science
Journal: PLoS ONE
Languages: English
Types: Article
Subjects: Genetics of the Immune System, Human genetics, Research Article, Variant genotypes, Rheumatology, Polymorphism, HLA-DRB1 Chains, Genetics, Observational Studies, Alleles, Autoimmune Diseases, Population Genetics, Genetics of disease, Biology, STAT4 Transcription Factor, Medicina, Clinical Research Design, Medicine, Rheumatoid Arthritis, Personalized Medicine, Q, R, Disabilities, Arthritis, Clinical Immunology, Science, Clinical Genetics, Genetic Polymorphism, Longitudinal Studies
Background: The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis. Methodology and Results: We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5′ allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype. Conclusions: Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability This work was partially supported by the RETICS (Redes Tematicas de Investigación Cooperativa, Cooperative Research Thematic Networks) Program, RD08/0075 (RIER) and FIS (Fondo de Investigación en Salud) Health Research Fund grant FIS 08/0754 to IG-A from Instituto de Salud Carlos III (ISCIII; www.isciii.es) and by grants from the European Innovative Medicines Initiative and BTCure Program (http://www.life-sciences-europe.com/organisation/btcure-project-imiefpia- 201103-innovative-medicines-initiative-2001-28657.html). The work of IG-A was in part supported by a Research Intensification Grant from the National Health Care System (Instituto Carlos III; www.isciii.es), Madrid, Spain
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    • 1. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, et al. (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43: 30-37.
    • 2. Orozco G, Rueda B, Martin J (2006) Genetic basis of rheumatoid arthritis. Biomed Pharmacother 60: 656-662.
    • 3. Gregersen PK, Olsson LM (2009) Recent advances in the genetics of autoimmune disease. Annu Rev Immunol 27: 363-391.
    • 4. Orozco G, Alizadeh BZ, Delgado-Vega AM, Gonzalez-Gay MA, Balsa A, et al. (2008) Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum 58: 1974-1980.
    • 5. Orozco G, Sanchez E, Gonzalez-Gay MA, Lopez-Nevot MA, Torres B, et al. (2005) Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 52: 219-224.
    • 6. Goronzy JJ, Matteson EL, Fulbright JW, Warrington KJ, Chang-Miller A, et al. (2004) Prognostic markers of radiographic progression in early rheumatoid arthritis. Arthritis Rheum 50: 43-54.
    • 7. Weyand CM, Xie C, Goronzy JJ (1992) Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis. J Clin Invest 89: 2033-2039.
    • 8. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, Schreuder GM, Ewals JA, et al. (2008) Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis Rheum 58: 1293-1298.
    • 9. Gonzalez-Gay MA, Gonzalez-Juanatey C, Lopez-Diaz MJ, Pineiro A, GarciaPorrua C, et al. (2007) HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum 57: 125-132.
    • 10. Marinou I, Maxwell JR, Wilson AG (2010) Genetic influences modulating the radiological severity of rheumatoid arthritis. Ann Rheum Dis 69: 476-482.
    • 11. Morgan AW, Robinson JI, Conaghan PG, Martin SG, Hensor EM, et al. (2010) Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort. Arthritis Res Ther 12: R57.
    • 12. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31: 315-324.
    • 13. Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, et al. (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38: 44-48.
    • 14. Esteve-Vives J, Batlle-Gualda E, Reig A (1993) Spanish version of the Health Assessment Questionnaire: reliability, validity and transcultural equivalency. Grupo para la Adaptacion del HAQ a la Poblacion Espanola. J Rheumatol 20: 2116-2122.
    • 15. Pan W (2001) Model selection in estimating equations. Biometrics 57: 529-534.
    • 16. Korman BD, Kastner DL, Gregersen PK, Remmers EF (2008) STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep 8: 398-403.
    • 17. Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, et al. (2009) Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J Immunol 182: 34- 38.
    • 18. Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, et al. (2008) Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 4: e1000084.
    • 19. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP (2011) Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett 585: 3689-3698.
    • 20. Scott DL, Houssien DA (1996) Joint assessment in rheumatoid arthritis. Br J Rheumatol 35 Suppl 2: 14-18.
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