COMonCA2011006

COM.on C.A.6:e6/34-38 Online published on Jan.17, 2012.
doi:10.4236/coca.2012.61006

REVIEW
The relationship between autoimmune diseases and STAT4 as well as its gene polymorphism

Ting Wu

MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China

ABSTRACT: STAT4 (signal transducer and activator for transcription) is a member of STAT protein family of transcription factors, which plays an important role in type I interferon (IFN) receptor signaling pathway and is a key mediator in the inflammatory stage of protective immune responses and immune-mediated diseases. In addition, STAT4 also takes an active part in various essential life processes such as cell proliferation, cytokine-mediated signal pathway, and protein phosphorylation. Recently, various gene relevant studies have found that STAT4 has several single nucleotide polymorphism (SNP) sites, which reveal a close relationship with pathological mechanism and progression of various autoimmune diseases. The difference among SNP sites in the population with different ethnic backgrounds may be contributed to different genetic structures of different ethnic groups.

Key words: STAT, autoimmune disease, single nucleotide polymorphism, transcription factor

STAT4及其基因多态性与自身免疫性疾病的关系

伍婷

复旦大学生命科学学院现代人类学教育部重点实验室，上海200433

摘要：STAT4(信号转导因子和转录激活因子)是STAT转录因子蛋白家族的一个转录因子蛋白，它在Ⅰ型干扰素受体信号转导途径中发挥重要作用，同时在保护性免疫反应以及免疫介导疾病的炎症阶段是一个重要的媒介。另外，STAT4在细胞增殖、细胞因子介导的信号途径以及蛋白磷酸化等重要的生命过程中占有举足轻重的地位。目前，众多基因关联研究发现STAT4存在多个单核苷酸多态性位点，并且与多种自身免疫性疾病的发生、发展都存在密切关联。其不同的多态性位点在不同人群中存在一定程度上的差异，可能是由于不同人群遗传结构上的差异导致的。

关键词：STAT；自身免疫；单核苷酸多态性；转录因子

收稿日期：2011年12月7日 修回日期：2011年12月9日 联系人：伍婷 shanbenjiumei@sina.com

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参考文献 References

1. Hoey T, Grusby MJ (1999) STATs as mediators of cytokine-induced responses. Adv Immunol 71:145-162.
2. Leonard WJ, O’shea JJ (1998) Jaks and STATs: biological implications. Annu Res Immunol 16:293-322.
3. O’shea JJ (1997) Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7:1-11.
4. Yamamoto K, Quelle FW, Thierfelder WE, Kreider BL, Gilbert DJ, Jenkins NA, Copeland NG, Silvennoinen O, Ihle JN (1994) Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation. Mol Cell Biol 14:4342-4349.
5. Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc Natl Acad Sci USA 91:4806-4810.
6. Cho SS, Bacon CM, Sudarshan C, Rees RC, Finbloom D, Pine R, O'Shea JJ (1996) Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine. J Immunol 157:4781-4789.
7. Szabo SJ, Dighe AS, Gubler U, Murphy KM (1997) Regulation of interlukine (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 185:817-824.
8. Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, Murphy TL, Murphy KM (1999) The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proc Natl Acad Sci USA 1999; 96:3888-3893.
9. Galon J, Sudarshan C, Ito S, Finbloom D, O'Shea JJ (1999) IL-12 induces IFN regulating factor -1 (IRF-1) gene expression in human NK and T cells. J Immunol 162:7256-7262.
10. Chung SA, Taylor KE, Graham RR, Nititham J, Lee AT, Ortmann WA, Jacob CO, Alarcón-Riquelme ME, Tsao BP, Harley JB, Gaffney PM, Moser KL; SLEGEN, Petri M, Demirci FY, Kamboh MI, Manzi S, Gregersen PK, Langefeld CD, Behrens TW, Criswell LA (2011) Differential genetic association for systemic lupus erythematosus based on anti-dsDNA autoantibody production. Plos Genet 7:e1001323.
11. Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, Chung SA, Nititham J, Hom G, Kao AH, Demirci FY, Kamboh MI, Petri M, Manzi S, Kastner DL, Seldin MF, Gregersen PK, Behrens TW, Criswell LA (2008) Specificity of the STAT4 genetic association for sever disease manifestations of systemic lupus erythematosus. Plos Genet 4:e1000084.
12. Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, Eloranta ML, Gunnarsson I, Svenungsson E, Sturfelt G, Bengtsson AA, Jönsen A, Truedsson L, Rantapää-Dahlqvist S, Eriksson C, Alm G, Göring HH, Pastinen T, Syvänen AC, Rönnblom L (2008) 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 17:2868-2876.
13. Kawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham RR, Hom G, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N (2008) Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region. Arthritis Res Ther 10:R113.
14. Li P, Cao C, Luan H, Li C, Hu C, Zhang S, Zeng X, Zhang F, Zeng C, Li Y (2011) Association of genetic variations in the STAT4 and IRF7/KIAA1542 regions with systemic lupus erythematosus in a Northern Han Chinese population. Hum Immunol 72:249-255.
15. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG (2010) Association between the rs7574865 polymorphism of STAT4 and rheumatoid arthritis: a meta-analysis. Rheumatol Int 30:661-666.
16. Liang YL, Wu H, Li PQ, Xie XD, Shen X, Yang XQ, 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 89:171-175.
17. 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 13:455-460.
18. Orozco G, Alizadeh BZ, Delgado-Vega AM, González-Gay MA, Balsa A, Pascual-Salcedo D, Fernández-Gutierrez B, González-Escribano MF, Petersson IF, van Riel PL, Barrera P, Coenen MJ, Radstake TR, van Leeuwen MA, Wijmenga C, Koeleman BP, Alarcón-Riquelme M, Martín J (2008) Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum 58:1974-1980.
19. Palomino-Morales RJ, Rojas-Villarraga A, González CI, Ramírez G, Anaya JM, Martín J (2008) STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Columbians. Genes Immun 9:397-382.
20. Zervou MI, Sidiropoulos P, Petraki E, Vazgiourakis V, Krasoudaki E, Raptopoulou A, Kritikos H, Choustoulaki E, Boumpas DT, Goulielmos GN (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.
21. 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 58:1940-1946.
22. 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. Rheummatology(Oxford) 48:1363-1368.
23. Dieudé P, Guedj M, Wipff J, Ruiz B, Hachulla E, Diot E, Granel B, Sibilia J, Tiev K, Mouthon L, Cracowski JL, Carpentier PH, Amoura Z, Fajardy I, Avouac J, Meyer O, Kahan A, Boileau C, Allanore Y (2009) STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Arthritis Rheum 60:2472-2479.
24. Tsuchiya N, Kawasaki A, Hasegawa M, Fujimoto M, Takehara K, Kawaguchi Y, Kawamoto M, Hara M, Sato S (2009) Association of STAT4 polymorphism with systemic sclerosis in a Japanese population. Ann Rheum Dis 68:1375-1376.
25. Gourh P, Agarwal SK, Divecha D, Assassi S, Paz G, Arora-Singh RK, Reveille JD, Shete S, Mayes MD, Arnett FC, Tan FK (2009) Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction in Th1/Th2 cytokines. Arthritis Rheum 60:3794-3806.
26. Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R, Coenen MJ, Vonk MC, Voskuyl AE, Schuerwegh AJ, Broen JC, van Riel PL, van 't Slot R, Italiaander A, Ophoff RA, Riemekasten G, Hunzelmann N, Simeon CP, Ortego-Centeno N, González-Gay MA, González-Escribano MF; Spanish Scleroderma Group, Airo P, van Laar J, Herrick A, Worthington J, Hesselstrand R, Smith V, de Keyser F, Houssiau F, Chee MM, Madhok R, Shiels P, Westhovens R, Kreuter A, Kiener H, de Baere E, Witte T, Padykov L, Klareskog L, Beretta L, Scorza R, Lie BA, Hoffmann-Vold AM, Carreira P, Varga J, Hinchcliff M, Gregersen PK, Lee AT, Ying J, Han Y, Weng SF, Amos CI, Wigley FM, Hummers L, Nelson JL, Agarwal SK, Assassi S, Gourh P, Tan FK, Koeleman BP, Arnett FC, Martin J, Mayes MD (2010) Genome-wide association study of systemic sclerosis identifies CD247as a new susceptibility locus. Nat Genet 2010; 42:426-429.
27. Rueda B, Broen J, Simeon C, Hesselstrand R, Diaz B, Suárez H, Ortego-Centeno N, Riemekasten G, Fonollosa V, Vonk MC, van den Hoogen FH, Sanchez-Román J, Aguirre-Zamorano MA, García-Portales R, Pros A, Camps MT, Gonzalez-Gay MA, Coenen MJ, Airo P, Beretta L, Scorza R, van Laar J, Gonzalez-Escribano MF, Nelson JL, Radstake TR, Martin J (2009) The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mole Geneti 18:2071-2077.
28. Avouac J, Fürnrohr BG, Tomcik M, Palumbo K, Zerr P, Horn A, Dees C, Akhmetshina A, Beyer C, Distler O, Schett G, Allanore Y, Distler JH (2011) Interaction of the transcription factor STAT4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum 63:800-809.