Terapevticheskii arkhivTerapevticheskii arkhiv0040-36602309-5342LLC Obyedinennaya Redaktsiya3218110.17116/terarkh201789520-25Research ArticleThe influence of STAT4 rs7574865 (G/T) polymorphism on the risk of clinical and immunological phenotypes of systemic sclerosis in a Russian patient population: Results of a pilot studyKrylovM Yu-AnanyevaL P-KonevaО А-StarovoytovaM N-DesinovaO V-OvsyannikovaO B-AleksandrovaE N-NovikovA A-GusevaI A-KonovalovaN V-VarlamovD A-15052017895202510042020Copyright © 2017, Consilium Medicum2017Aim. To examine the association of signal transducer and activator transcription 4 (STAT4) rs7574865 G/T polymorphism with a predisposition to systemic sclerosis (SSC) and associated clinical and autoimmune phenotypes in a Russian population. Subjects and methods. A total of 102 patients with SSC and 103 healthy individuals as controls were examined. STAT4 rs7574865 polymorphism was investigated by real-time polymerase chain reaction. Results. The carriers of the T allele showed a statistically significant association with SSC, a diffuse form (DF), the presence of interstitial lung disease (ILD), cardiac injury (CI), and seropositivity for anti-topoisomerase I antibodies (ATA). Conclusion. The findings results confirm the important role of STAT4 gene in the predisposition to SSC and its phenotypes, such as DF, ILD, CI, and ATA in the Russian population.systemic sclerosisgeneticspolymorphismSTAT4 genepopulationсистемная склеродермиягенетикаполиморфизмген STAT4популяция[Stephanie GY, Kong J, Cheema GS, Keen CL, Wick G, Gershwin ME. The immunobiology of systemic sclerosis. Semin Arthritis Rheum. 2008;38:132-160. doi:10.1016/j.semarthrit.2007.10.010][Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40:204-210. doi:10.1016/j.clim.2008.03.252][Korman BD, Alba MI, Le JM, Alevizos I, Smith JA, Nikolov NP, et al. Variant form of STAT4 is associated with primary Sjo¨gren’s syndrome. Genes Immun. 2008;9:267-270. doi:10.1038/gene.2008.1][Martinez A, Varade J, Marquez A, Cenit MC, Espino L, Perdigones N, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum. 2008; 58:2598-2602. doi:10.1002/art.23792][Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357:977-986. doi:10.1056/nejmoa073003][Kobayashi S, Ikari K, Kaneko H, Kochi Y, Yamamoto K, Shimane K, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum. 2008;58:1940-1946. doi:10.1002/art.23494][Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med. 2007;13:455-460. doi:10.2119/2007-00072.Lee][Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004;202:139-156. doi:10.1111/j.0105-2896.2004.00211x][Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, et al. A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet. 2008;17:2868-2876. doi:10.1093/hmg/ddn184][Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557-567. doi:10.1172/JCI31139][Bunn CC, Black CM. Systemic sclerosis: an autoantibody mosaic. Clin ExpImmunol. 1999;117:207. doi:10.1046/j.1365-2249.1999.00990.x][Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35:35-42. doi:10.1016/j.semarthrit.2005.03.005][Arnett FC, Howard RF, Tan F., et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum. 1996;39:1362-1370. doi:10.1002/art.1780390814][Steen V, Domsic RT, Lucas M, Fertig N, Medsger TA. A clinical and serologic comparison of African-American and Caucasian patients with systemic sclerosis. Arthritis Rheum. 2012;64(9): 2986-2995. doi:10.1002/art.34482][Wang J, Assassi S, Guo G, et al. Clinical and serological features of systemic sclerosis in a Chinese cohort. Clin Rheumatol. 2013;32(5):617-621. doi:10.1007/s10067-012-2145-7][Radstake TR, Gorlova O, Rueda B, et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet. 2010;42(5):426-429. doi:10.1038/ng.565][Thierfelder WE, van Deursen JM, Yamamoto K. et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996;382(6487):171-174. doi:10.1038/382171a0][Rueda B, Broen J, Simeon C. et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet. 2009; 18:2071-2077. doi:10.1093/hmg/ddp119][Tsuchiya N, Kawasaki A, Hasegawa M. et al. Association of STAT4 polymorphism with systemic sclerosis in a Japanese population. Ann Rheum Dis. 2009;68(8):1375-1376. doi:10.1136/ard.2009.111310][Yi L,Wang JC, Guo XJ, Gu YH. et al. STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. Int J Immunopathol Pharmacol. 2013;26(2):473-478.][Fukao T, Frucht DM, Yap G, Gadina M, O’Shea JJ, Koyasu S. Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J Immunol. 2001;166:4446-4455. doi:10.4049/jimmunol.166.7.4446][Avouac J, Fürnrohr BG, Tomcik M., et al. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum. 2011; 63:800-809. doi:10.1002/art.30171]