Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease in whose etiology genetic factors are known to play an important role. Among the genes associated with RA, STAT4 could be an important factor in conducting helper T cells toward the pro-inflammatory Th1 and Th17 lineages. The aim of this study is to determine the association of the STAT4 polymorphism rs7574865 with RA, disease activity, and anti-cyclic citrullinated peptide (CCP) antibody levels in a Mexican population. Genotyping was carried out using the Taqman® system from Applied Biosystems in 140 patients with RA and 150 healthy subjects. Disease activity was evaluated by a rheumatologist using the DAS28 and Spanish-HAQ-DI instruments. Anti-CCP levels were determined by ELISA. Associations of the genotypes of rs7574865 with DAS28, HAQ, and anti-CCP antibody levels with RA were determined. Findings showed that the GT and TT genotypes and the T allele from rs7574865 were all associated as risk factors for RA, independently of their anti-CCP status. An association with moderate-to-high disease activity (DAS28 ≥ 3.2) was also found. Additionally, patients with the GT or TT genotypes showed lower HAQ values than those who carried the GG genotype. No differences in anti-CCP antibody levels or DAS28 and genotypes were found. This work supports the association of the STAT4 rs7574865 polymorphism with RA and disease activity, but not with anti-CCP antibody levels in a Mexican population.
Similar content being viewed by others
References
Paradowska-Gorycka A, Grzybowska-Kowalczyk A, Wojtecka-Lukasik E, Maslinski S (2010) IL-23 in the pathogenesis of rheumatoid arthritis. Scand J Immunol 71(3):134–145. doi:10.1111/j.1365-3083.2009.02361.x
Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK (2007) Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med 13(9–10):455–460. doi:10.2119/2007-00072.Lee
Burgos-Vargas R, Catoggio LJ, Galarza-Maldonado C, Ostojich K, Cardiel MH (2013) Current therapies in rheumatoid arthritis: a Latin American perspective. Reumatol Clin 9(2):106–112. doi:10.1016/j.reuma.2012.09.001
Boissier M-C, Semerano L, Challal S, Saidenberg-Kermanac’h N, Falgarone G (2012) Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. J Autoimmun 39(3):222–228. doi:10.1016/j.jaut.2012.05.021
Sakkas LI, Bogdanos DP, Katsiari C, Platsoucas CD (2014) Anti-citrullinated peptides as autoantigens in rheumatoid arthritis—relevance to treatment. Autoimmun Rev 13(11):1114–1120. doi:10.1016/j.autrev.2014.08.012
Orozco G, Alizadeh BZ, Delgado-Vega AM, Gonzalez-Gay MA, Balsa A, Pascual-Salcedo D, Fernandez-Gutierrez B, Gonzalez-Escribano MF, Petersson IF, van Riel PL, Barrera P, Coenen MJ, Radstake TR, van Leeuwen MA, Wijmenga C, Koeleman BP, Alarcon-Riquelme M, Martin J (2008) Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum 58(7):1974–1980. doi:10.1002/art.23549
Kobayashi S, Ikari K, Kaneko H, Kochi Y, Yamamoto K, Shimane K, Nakamura Y, Toyama Y, Mochizuki T, Tsukahara S, Kawaguchi Y, Terai C, Hara M, Tomatsu T, Yamanaka H, Horiuchi T, Tao K, Yasutomo K, Hamada D, Yasui N, Inoue H, Itakura M, Okamoto H, Kamatani N, Momohara S (2008) Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 58(7):1940–1946. doi:10.1002/art.23494
Li H, Zou Q, Xie Z, Liu Y, Zhong B, Yang S, Zheng P, Yang F, Fang Y, Wu Y (2009) A haplotype in STAT4 gene associated with rheumatoid arthritis in Caucasians is not associated in the Han Chinese population, but with the presence of rheumatoid factor. Rheumatology (Oxford) 48(11):1363–1368. doi:10.1093/rheumatology/kep207
Nishikomori R, Usui T, Wu C-Y, Morinobu A, O’Shea JJ, Strober W (2002) Activated STAT4 has an essential role in Th1 differentiation and proliferation that is independent of its role in the maintenance of IL-12Rβ2 chain expression and signaling. J Immunol 169(8):4388–4398. doi:10.4049/jimmunol.169.8.4388
Imboden JB (2009) The immunopathogenesis of rheumatoid arthritis. Annu Rev Pathol 4(1):417–434. doi:10.1146/annurev.pathol.4.110807.092254
Korman BD, Kastner DL, Gregersen PK, Remmers EF (2008) STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep 8(5):398–403
Shen L, Liu R, Zhang H, Huang Y, Sun R, Tang P (2013) Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a Chinese population. Gene 526(2):259–264. doi:10.1016/j.gene.2013.05.022
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357(10):977–986. doi:10.1056/NEJMoa073003
Fodil M, Benzaoui A, Zemani-Fodil F, Aberkane M, Boughrara W, Saidi-Mehtar N, Petit-Teixeira E, Boudjema A (2015) Association of PTPN22 (rs2476601) and STAT4 (rs7574865) polymorphisms with rheumatoid arthritis in the Western Algerian population. Acta Reumatol Port 40(1):56–62
Settin A, Salama A, Elshazli R (2014) Signal transducer and activator of transcription 4 (STAT4) G>T gene polymorphism in Egyptian cases with rheumatoid arthritis. Hum Immunol 75(8):863–866. doi:10.1016/j.humimm.2014.06.013
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580–1588. doi:10.1136/ard.2010.138461
Cardiel MH, Abello-Banfi M, Ruiz-Mercado R, Alarcon-Segovia D (1993) How to measure health status in rheumatoid arthritis in non-English speaking patients: validation of a Spanish version of the Health Assessment Questionnaire Disability Index (Spanish HAQ-DI). Clin Exp Rheumatol 11(2):117–121
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215
Zambrano-Zaragoza JF, Romo-Martínez EJ, Durán-Avelar MJ, García-Magallanes N, Vibanco-Pérez N (2014) Th17 cells in autoimmune and infectious diseases. Int J Inflamm 2014:12. doi:10.1155/2014/651503
Mohamed RH, Pasha HF, El-Shahawy EE (2012) Influence of TRAF1/C5 and STAT4 genes polymorphisms on susceptibility and severity of rheumatoid arthritis in Egyptian population. Cell Immunol 273(1):67–72. doi:10.1016/j.cellimm.2011.11.005
Palomino-Morales RJ, Rojas-Villarraga A, Gonzalez CI, Ramirez G, Anaya JM, Martin J (2008) STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians. Genes Immun 9(4):379–382. doi:10.1038/gene.2008.30
Gardette A, Ottaviani S, Tubach F, Roy C, Nicaise-Roland P, Palazzo E, Gill G, Meyer O, Dieudé P (2014) High anti-CCP antibody titres predict good response to rituximab in patients with active rheumatoid arthritis. Joint Bone Spine 81(5):416–420. doi:10.1016/j.jbspin.2014.06.001
Hensvold AH, Joshua V, Li W, Larkin M, Qureshi F, Israelsson L, Padyukov L, Lundberg K, Defranoux N, Saevarsdottir S, Catrina AI (2015) Serum RANKL levels associate with anti- citrullinated protein antibodies in early untreated rheumatoid arthritis and are modulated following methotrexate. Arthritis Res Ther 17(1478–6362 (Electronic)):239. doi:10.1186/s13075-015-0760-9
Inui N, Enomoto N, Suda T, Kageyama Y, Watanabe H, Chida K (2008) Anti-cyclic citrullinated peptide antibodies in lung diseases associated with rheumatoid arthritis. Clin Biochem 41(13):1074–1077. doi:10.1016/j.clinbiochem.2008.06.014
Elshazli R, Settin A (2015) Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: a meta-analysis update. Immunobiology 220(8):1012–1024. doi:10.1016/j.imbio.2015.04.003
Daha NA, Kurreeman FAS, Marques RB, Stoeken-Rijsbergen G, Verduijn W, Huizinga TWJ, Toes REM (2009) Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum 60(5):1255–1260. doi:10.1002/art.24503
Ben Hamad M, Cornelis F, Mbarek H, Chabchoub G, Marzouk S, Bahloul Z, Rebai A, Fakhfakh F, Ayadi H, Petit-Teixeira E, Maalej A (2011) Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders. Clin Exp Rheumatol 29(2):269–274
Seddighzadeh M, Gonzalez A, Ding B, Ferreiro-Iglesias A, Gomez-Reino JJ, Klareskog L, Alfredsson L, Dunussi-Joannopoulos K, Clark JD, Padyukov L (2012) Variants within STAT genes reveal association with anticitrullinated protein antibody-negative rheumatoid arthritis in 2 European populations. J Rheumatol 39(8):1509–1516. doi:10.3899/jrheum.111284
Liang Y-l WH, P-q L, Xie X-d, Shen X, Yang X-q, Cheng X, Liang L (2011) Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in Northwestern Chinese Han population. Life Sci 89(5–6):171–175. doi:10.1016/j.lfs.2011.05.012
Abelson AK, Delgado-Vega AM, Kozyrev SV, Sanchez E, Velazquez-Cruz R, Eriksson N, Wojcik J, Linga Reddy MV, Lima G, D’Alfonso S, Migliaresi S, Baca V, Orozco L, Witte T, Ortego-Centeno N, Abderrahim H, Pons-Estel BA, Gutierrez C, Suarez A, Gonzalez-Escribano MF, Martin J, Alarcon-Riquelme ME (2009) STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann Rheum Dis 68(11):1746–1753. doi:10.1136/ard.2008.097642
Acknowledgments
This work was supported by the Integral Program for Institutional Improvement (PIFI-2011-18MSU0019M-05) and the Improvement of Quality of Educational Institutions Program (PROFOCIE-2014-18MSU0019M-04-01). Raquel Rocío Hernández Pacheco was funded as a Fellow of Mexico’s National Science and Technology Council (CONACYT), while América del Carmen Castro Zambrano was a Fellow of the National Organization for Scholarships for Higher Education of Mexico’s Department of Public Education (SEP).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosures
None.
Rights and permissions
About this article
Cite this article
Durán-Avelar, M.d.J., Vibanco-Pérez, N., Hernández-Pacheco, R.R. et al. STAT4 rs7574865 G/T polymorphism is associated with rheumatoid arthritis and disease activity, but not with anti-CCP antibody levels in a Mexican population. Clin Rheumatol 35, 2909–2914 (2016). https://doi.org/10.1007/s10067-016-3320-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-016-3320-z