The role of PTPN22 rs2476601 and STAT4 rs7574865 gene polymorphism in the incidence of rheumatoid arthritis
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory condition that often affects many peripheral joints. It is characterized by a faulty immune system. This autoimmune disorder affects 1% of the population, with women having double the risk as men. Numerous signs point to the idea that genetics play an important role in the beginning of RA. Previous studies reported that some of the non HLA genes such as PTPN22 and STAT4 could be risk factors for the development of autoimmune diseases, including RA. The purpose of this study was to demonstrate the relationship between the single nucleotide polymorphisms, PTPN22 rs2476601 and STAT4 rs7574865, and a higher risk of RA illness in the population of AL-Dewaniya, Iraq as well as the possibility of galectin 3 associating with the minor allele. One hundred and fifty participants were involved in this study; seventy-five of them were RA patients and the others were clinically healthy control. Blood samples were collected from both study groups and separated into 2 mL in EDTA tubes for genotypic study and 3 mL in gel tube for serological study (Gal-3). According to the results obtained, the frequencies of PTPN22 rs2476601 G allele were 73 out of 150 (48.7%), 94 out of 150 (62.7%), while the frequencies of PTPN22 rs2476601 A allele were 77 out of 150 (51.3%) and 56 out of 150 (37.3%) for RA and control respectively. The most prevalent genotype of PTPN22 gene frequency was heterozygous (GA) followed by homozygous mutant (AA), then homozygous wild-type (GG). The STAT4 rs7574865 G allele frequencies were 121 out of 150 (80.7%), 139 out of 150 (92.3%), whereas the STAT4 rs7574865 T allele frequencies were 29 out of 150 (19.3%) and 11 out of 150 (7.3%) for RA and control respectively. The most prevalent genotype of STAT4 gene frequency was the homozygous wild-type (GG) followed by the heterozygous (GT), then the homozygous mutant (TT). The observed results indicate that there is an association between PTPN22 minor allele (A) and STAT4 minor allele (T) with RA. Additionally, for the first time, the study investigated the relationship between Gal-3 (positive results) with minor alleles of the both genes, which shows an association between both minor alleles of both genes’ polymorphism and high serum levels (positive results) of galectin-3 (Gal-3).References
Abbasi, Z., Kazemi Nezhad, S. R., Pourmahdi-Broojeni, M., & Rajaei, E. (2017). Association of PTPN22 rs2476601 polymorphism with rheumatoid arthritis and celiac disease in Khuzestan Province, Southwestern Iran. Iranian Biomedical Journal, 21(1), 61–66.
Abbasifard, M., Imani, D., & Bagheri‐Hosseinabadi, Z. (2020). PTPN22 gene polymorphism and susceptibility to rheumatoid arthritis (RA): Updated systematic review and meta-analysis. The Journal of Gene Medicine, 22(9), e3204.
Alizadeh, Z., Farazmand, A., Akhlaghi, M., Jamshidi, A. R., Shahlaee, A., Karami, J., Shamsian, E., & Mahmoudi, M. (2016). STAT4 rs7574865 polymorphism in Iranian patients with rheumatoid arthritis. Indian Journal of Rheumatology, 11(2), 78–81.
Almurshedi, S. M., Alasady, R. A. A., Alsherees, H. A., Almohana, A. M., Aljayashi, K. G., & Almudhaffer, D. H. (1970). The role of galectin-3 in the diagnosis and evaluation of disease activity in rheumatoid arthritis. Jurnal Biota, 9(2), 118–126.
Arnett, F. C., Edworthy, S. M., Bloch, D. A., Mcshane, D. J., Fries, J. F., Cooper, N. S., Healey, L. A., Kaplan, S. R., Liang, M. H., Luthra, H. S., Medsger, T. A., Mitchell, D. M., Neustadt, D. H., Pinals, R. S., Schaller, J. G., Sharp, J. T., Wilder, R. L., & Hunder, G. G. (1988). The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis and Rheumatism, 31(3), 315–324.
Bin Huraib, G., Al Harthi, F., Arfin, M., Rizvi, S., & Al-Asmari, A. (2018). The protein tyrosine phosphatase nonreceptor 22 (PTPN22) R620W functional polymorphism in psoriasis. In: Clinical medicine insights: Arthritis and musculoskeletal disorders. IntechOpen, London. Vol. 11. Article 117954411775143.
Blekeris, T., Gedvilaite, G., Kaikaryte, K., Kriauciuniene, L., Zaliuniene, D., & Liutkevciene, R. (2023). Association of STAT4 gene polymorphisms (rs10181656, rs7574865, rs7601754, rs10168266) and serum STAT4 levels in age-related macular degeneration. Biomedicines, 12(1), 18.
Bravo-Villagra, K. M., Muñoz-Valle, J. F., Baños-Hernández, C. J., Cerpa-Cruz, S., Navarro-Zarza, J. E., Parra-Rojas, I., Aguilar-Velázquez, J. A., García-Arellano, S., & López-Quintero, A. (2024). STAT4 gene variant rs7574865 is associated with rheumatoid arthritis activity and anti-CCP levels in the western but not in the southern population of Mexico. Genes, 15(2), 241.
de Oliveira, F. L., Gatto, M., Bassi, N., Luisetto, R., Ghirardello, A., Punzi, L., & Doria, A. (2015). Galectin-3 in autoimmunity and autoimmune diseases. Experimental Biology and Medicine, 240(8), 1019–1028.
Deane, K. D., Demoruelle, M. K., Kelmenson, L. B., Kuhn, K. A., Norris, J. M., & Holers, V. M. (2017). Genetic and environmental risk factors for rheumatoid arthritis. Best Practice and Research Clinical Rheumatology, 31(1), 3–18.
Durán-Avelar, M. de J., Vibanco-Pérez, N., Hernández-Pacheco, R. R., Castro-Zambrano, A. del C., Ortiz-Martínez, L., & Zambrano-Zaragoza, J. F. (2016). STAT4 rs7574865 G/T polymorphism is associated with rheumatoid arthritis and disease activity, but not with anti-CCP antibody levels in a Mexican population. Clinical Rheumatology, 35(12), 2909–2914.
El-Lebedy, D., Raslan, H., Ibrahim, A., Ashmawy, I., El-Aziz, S. A., & Mohammed, A. M. (2017). Association of STAT4 rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoid arthritis and non-systemically reacting antibodies in Egyptian patients. Clinical Rheumatology, 36(9), 1981–1987.
Esparza Guerrero, Y., Vazquez Villegas, M. L., Nava Valdivia, C. A., Ponce Guarneros, J. M., Perez Guerrero, E. E., Gomez Ramirez, E. E., Ramirez Villafaña, M., Contreras Haro, B., Martinez Hernandez, A., Cardona Muñoz, E. G., Nuño Arana, I., Gallardo Moya, S. G., Celis, A., Gonzalez Lopez, L., Gamez Nava, J. I., & Saldaña Cruz, A. M. (2023). Association of the STAT4 gene rs7574865 polymorphism with IFN-γ levels in patients with systemic lupus erythematosus. Genes, 14(3), 537.
Galita, G., Sarnik, J., Brzezinska, O., Budlewski, T., Poplawska, M., Sakowski, S., Dudek, G., Majsterek, I., Makowska, J., & Poplawski, T. (2024). The association between inefficient repair of DNA double-strand breaks and common polymorphisms of the HRR and NHEJ repair genes in patients with rheumatoid arthritis. International Journal of Molecular Sciences, 25(5), 2619.
Goswami, R., & Kaplan, M. H. (2017). STAT transcription factors in T cell control of health and disease. International Review of Cell and Molecular Biology, 331, 123–180.
Gruszewska, E., Cylwik, B., Gińdzieńska-Sieśkiewicz, E., Kowal-Bielecka, O., Mroczko, B., & Chrostek, L. (2020). Diagnostic power of galectin-3 in rheumatic diseases. Journal of Clinical Medicine, 9(10), 3312.
Gupta, G. S. (2012). Animal lectins: Form, function and clinical applications. Springer, Vienna.
Hameed Neamaa, G., Raheem Tarish, H., & Azeez Addoos, S. (2018). Association between gene polymorphism of protein tyrosin phosphatase non receptor type 22 (PTPN22) and susceptibility for rheumatoid arthritis in an Iraqi population. Journal of Kerbala University, 14(1), 28–35.
Hasan, A. A., Khudhur, H. R., Hameed, A. K., & Abed, S. M. (2022). Role of signal transducer, and activator of the transcription 4 (STAT4) gene polymorphism as predictive marker for type-1 autoimmune hepatitis. International Journal of Health Sciences, 6(S5), 6960–6969.
Hou, X., Qu, H., Zhang, S., Qi, X., Hakonarson, H., Xia, Q., & Li, J. (2020). The multi-omics architecture of juvenile idiopathic arthritis. Cells, 9(10), 2301.
Jasiem, T. M. (2022). Analysis of some candidate genes for rheumatoid arthritis of the Iraqi population. International Journal of Drug Delivery Technology, 12(1), 194–197.
Jeon, S.-B., Yoon, H. J., Chang, C. Y., Koh, H. S., Jeon, S.-H., & Park, E. J. (2010). Galectin-3 exerts cytokine-like regulatory actions through the JAK–STAT pathway. The Journal of Immunology, 185(11), 7037–7046.
Kang, C. (2015). Genetic studies of rheumatoid arthritis: Progress and challenges. Journal of Rheumatic Diseases, 22(5), 274–281.
Klak, M., Gomółka, M., Kowalska, P., Cichoń, J., Ambrożkiewicz, F., Serwańska-Świętek, M., Berman, A., & Wszoła, M. (2020). Type 1 diabetes: Genes associated with disease development. Central European Journal of Immunology, 45(4), 439–453.
Mendez-Huergo, S. P., Hockl, P. F., Stupirski, J. C., Maller, S. M., Morosi, L. G., Pinto, N. A., Berón, A. M., Musuruana, J. L., Nasswetter, G. G., Cavallasca, J. A., & Rabinovich, G. A. (2019). Clinical relevance of galectin-1 and galectin-3 in rheumatoid arthritis patients: Differential regulation and correlation with disease activity. Frontiers in Immunology, 9, 3057.
Mikhaylenko, D. S., Nemtsova, M. V., Bure, I. V., Kuznetsova, E. B., Alekseeva, E. A., Tarasov, V. V., Lukashev, A. N., Beloukhova, M. I., Deviatkin, A. A., & Zamyatnin, A. A. (2020). Genetic polymorphisms associated with rheumatoid arthritis development and antirheumatic therapy response. International Journal of Molecular Sciences, 21(14), 4911.
Nezaratian, N., Kazemi Nezhad, S. R., Hajjari, M., & Akhoond, M. R. (2017). Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene, 14, 64–68.
Nielsen, M., Køster, D., Greisen, S., Troldborg, A., Stengaard-Pedersen, K., Junker, P., Hørslev-Petersen, K., Hetland, M., Østergaard, M., Hvid, M., Leffler, H., Kragstrup, T., & Deleuran, B. (2022). Increased synovial galectin-3 induce inflammatory fibroblast activation and osteoclastogenesis in patients with rheumatoid arthritis. Scandinavian Journal of Rheumatology, 52(1), 33–41.
Orozco, G., Alizadeh, B. Z., Delgado-Vega, A. M., González-Gay, M. Á., Balsa, A., Pascual-Salcedo, D., Fernández-Gutierrez, B., González-Escribano, M. F., Petersson, I. F., van Riel, P. L. C. M., Barrera, P., Coenen, M. J. H., Radstake, T. R. D. J., van Leeuwen, M. A., Wijmenga, C., Koeleman, B. P. C., Alarcón‐Riquelme, M., & Martín, J. (2008). Association of STAT4 with rheumatoid arthritis: A replication study in three European populations. Arthritis and Rheumatism, 58(7), 1974–1980.
Padyukov, L., & Alfredsson, L. (2014). Gene–gene and gene–environment interaction in rheumatoid arthritis. In: Padyukov, L. (Ed.). Between the lines of genetic code. Genetic interactions in understanding disease and complex phenotypes. Academic Press, Cambridge. Pp. 85–100.
Pedersen, K., Nielsen, M. A., Juul-Madsen, K., Hvid, M., Deleuran, B., & Greisen, S. R. (2022). Galectin-3 interacts with PD-1 and counteracts the PD-1 pathway-driven regulation of T cell and osteoclast activity in rheumatoid arthritis. Scandinavian Journal of Immunology, 97(2), e13245.
Pisetsky, D. S. (2023). Pathogenesis of autoimmune disease. Nature Reviews Nephrology, 19(8), 509–524.
Schulz, S., Zimmer, P., Pütz, N., Jurianz, E., Schaller, H.-G., & Reichert, S. (2020). rs2476601 in PTPN22 gene in rheumatoid arthritis and periodontitis – a possible interface? Journal of Translational Medicine, 18(1), 389.
Shakir, T. (2020). Correlation of calprotectin with galectin 33, adropin and CTLA-4 in Iraqi rheumatoid arthritis patients. International Journal of Pharmaceutical Research, 12(1), 52.
Srejovic, I. M., & Lukic, M. L. (2021). Galectin-3 in T cell-mediated immunopathology and autoimmunity. Immunology Letters, 233, 57–67.
Tizaoui, K., Shin, J. I., Jeong, G. H., Yang, J. W., Park, S., Kim, J. H., Hwang, S. Y., Park, S. J., Koyanagi, A., & Smith, L. (2022). Genetic polymorphism of PTPN22 in autoimmune diseases: A comprehensive review. Medicina, 58(8), 1034.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons «Attribution» 4.0 License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
