Assessing the association of rs7574865 STAT4 gene variant and type 1 diabetes mellitus among Egyptian patients

Samar Samir Abdelmajed1, Mohamed A. El-Dessouky2, Doaa S. SalahElDin2, Naglaa Abu-Mandil Hassan3, Moushira Erfan Zaki3, Somaia Ismail4
1Modern Sciences and Arts University (MSA), Giza, Egypt
2Chemistry Department (Biochemistry Division), Faculty of Science, Cairo University, Giza, Egypt
3Biological Anthropology Department, Medical Research Division, National Research Centre, Giza, Egypt
4Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Giza, Egypt

Tóm tắt

Variants in the signal transducer and activator of transcription 4 (STAT4) gene have an important role in the incident of multiple autoimmune diseases including type 1 diabetes mellitus (T1D). It is a genetically related auto-immune disorder that resulted from T cell-mediated destruction of pancreatic cells that are in control for the production of insulin in the blood. The current study aimed to clarify the role of STAT4 (rs7574865) variant allelic and genotypic variations in the susceptibility to type 1 diabetes among Egyptians by using the real-time PCR. A total of 100 patients and 100 controls were genotyped for rs7574865, and the biochemical and anthropometric parameters were measured to show that type 1 diabetic patients had significantly higher levels of HbA1c and triglycerides compared to non-diabetic individuals (P < 0.05). And genetically, the T allele and GT genotype have a significant correlation with diabetes type 1. It was confirmed by this study that the rs7574865 T allele and GT genotype have a significant correlation with diabetes type 1 incidence among Egyptian patients.

Tài liệu tham khảo

Borchers AT, Uibo R, Gershwin ME (2010) The geoepidemiology of type 1 diabetes. Autoimmun Rev 9(5):A355–A365. https://doi.org/10.1016/j.autrev.2009.12.003 Federation ID (2017) IDF diabetes atlas 8th edition. International Diabetes Federation, pp 905–911 Harrington LE, Mangan PR, Weaver CT (2006) Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 18(3):349–356. https://doi.org/10.1016/j.coi.2006.03.017 Donaghue KC, Chiarelli F, Trotta D, Allgrove J, Dahl-Jorgensen K (2009) Microvascular and macrovascular complications associated with diabetes in children and adolescents. Pediatr Diabetes 10:195–203. https://doi.org/10.1111/j.1399-5448.2009.00576.x Goyal R, Jialal I (2020) Diabetes Mellitus Type 2. StatPearls. StatPearls Publishing, Treasure Island Størling J, Pociot F (2017) Type 1 diabetes candidate genes linked to pancreatic islet cell inflammation and beta-cell apoptosis. Genes 8(2):72. https://doi.org/10.3390/genes8020072 Aly TA, Ide A, Jahromi MM, Barker JM, Fernando MS, Babu SR, Eisenbarth GS (2006) Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci 103(38):14074–14079. https://doi.org/10.1073/pnas.0606349103 Braun L (2002) Race, ethnicity, and health: can genetics explain disparities? Perspect Biol Med 45(2):159–174. https://doi.org/10.1353/pbm.2002.0023 Lonard WJ, O'Shea JJ (1998) Jaks and STATs: biological implications. Annu Rev Immunol 16(1):293–322. https://doi.org/10.1146/annurev.immunol.16.1.293 Visconti R, Gadina M, Chiariello M, Chen EH, Stancato LF, Gutkind JS, O'Shea JJ (2000) Importance of the MKK6/p38 pathway for interleukin-12–induced STAT4 serine phosphorylation and transcriptional activity. Blood 96(5):1844–1852. https://doi.org/10.1182/blood.V96.5.1844 Decker T, Kovarik P (2000) Serine phosphorylation of STATs. Oncogene 19(21):2628–2637. https://doi.org/10.1038/sj.onc.1203481 Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L (1995) Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 181(2):817–821. https://doi.org/10.1084/jem.181.2.817 Rothe H, O'Hara RM, Martin S, Kolb H (1997) Suppression of cyclophosphamide induced diabetes development and pancreatic Th1 reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12 (p40) 2. Diabetologia 40(6):641–646. https://doi.org/10.1007/s001250050728 Rothe H, Burkart V, Faust A, Kolb H (1996) Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice. Diabetologia 39(1):119–122. https://doi.org/10.1007/BF00400422 Martinez A, Varade J, Marquez A, Cenit MC, Espino L, Perdigones N et al (2008) Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 58(9):2598–2602. https://doi.org/10.1002/art.23792 Kroke A, Bergmann MM, Lotze G, Jeckel A, Klipstein-Grobusch K, Boeing H (1999) Measures of quality control in the German component of the EPIC study. Ann Nutr Metab 43(4):216–224. https://doi.org/10.1159/000012788 Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063. https://doi.org/10.1074/jbc.R700016200 Stark GR, Darnell JE Jr (2012) The JAK-STAT pathway at twenty. Immunity 36(4):503–514. https://doi.org/10.1016/j.immuni.2012.03.01 O’Shea JJ, Plenge R (2012) JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36(4):542–550. https://doi.org/10.1016/j.immuni.2012.03.014 Zouidi F, Bouzid D, Fourati H, Fakhfakh R, Kammoun T, Hachicha M, Masmoudi H (2017) CREM variant rs17583959 conferred susceptibility to T1D risk in the Tunisian families. Immunol Lett 181:1–5. https://doi.org/10.1016/j.imlet.2016.11.007 Benmansour J, Stayoussef M, Al-Jenaidi FA, Rajab MH, Rayana CB, Said HB et al (2010) Association of single nucleotide polymorphisms in cytotoxic T-lymphocyte antigen 4 and susceptibility to autoimmune type 1 diabetes in Tunisians. Clin Vaccine Immunol 17(9):1473–1477. https://doi.org/10.1128/CVI.00099-10 Ferjeni Z, Bouzid D, Fourati H, Stayoussef M, Abida O, Kammoun T, Hachicha M, Penha-Gonçalves C, Masmoudi H (2015) Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: family based association study. Immunol Lett 163(1):1–7. https://doi.org/10.1016/j.imlet.2014.11.005 Mosaad YM, Auf FA, Metwally SS, Elsharkawy AA, El-Hawary AK, Hassan RH, Tawhid ZE, El-Chennawi FA (2012) HLA-DQB1* alleles and genetic susceptibility to type 1 diabetes mellitus. World J Diabetes 3(8):149–155. https://doi.org/10.4239/wjd.v3.i8.149 Wafai RJE, Chmaisse HN, Makki RF, Fakhoury H (2011) Association of HLA class II alleles and CTLA-4 polymorphism with type 1 diabetes. Saudi J Kidney Dis Transpl 22(2):273 Ahmed NS (2014) The codon 17 polymorphism of the CTLA4 gene in type 1 diabetes mellitus in the Baghdad population. J Med Genet Genom 6(1):1–5 Kobayashi S, Ikari K, Kaneko H, Kochi Y, Yamamoto K, Shimane K, 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. https://doi.org/10.1002/art.23494 Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, Criswell LA (2008) Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 4(5):e1000084. https://doi.org/10.1371/journal.pgen.1000084 Korman BD, Kastner DL, Gregersen PK, Remmers EF (2008) STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep 8(5):398–403. https://doi.org/10.1007/s11882-008-0077-8 Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178(8):4901–4907. https://doi.org/10.4049/jimmunol.178.8.4901 Zervou MI, Goulielmos GN, Castro-Giner F, Tosca AD, Krueger-Krasagakis S (2009) STAT4 gene polymorphism is associated with psoriasis in the genetically homogeneous population of Crete, Greece. Hum Immunol 70(9):738–741. https://doi.org/10.1016/j.humimm.2009.05.008 Holz A, Bot A, Coon B, Wolfe T, Grusby MJ, von Herrath MG (1999) Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence. J Immunol 163(10):5374–5382 Orozco G, Alizadeh BZ, Delgado-Vega AM, González-Gay MÁ, Balsa A, Pascual-Salcedo D, Martín J (2008) Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum 58(7):1974–1980. https://doi.org/10.1002/art.23549 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. https://doi.org/10.1016/j.humimm.2014.06.013 Yan N, Meng S, Zhou J, Xu J, Muhali FS, Jiang W et al (2014) Association between STAT4 gene polymorphisms and autoimmune thyroid diseases in a Chinese population. Int J Mol Sci 15(7):12280–12293. https://doi.org/10.3390/ijms150712280 Gao X, Wang J, Yu Y (2019) The association between STAT4 rs7574865 polymorphism and the susceptibility of autoimmune thyroid disease: a meta-analysis. Front Genet 9:708. https://doi.org/10.3389/fgene.2018.00708 Dieudé P, Guedj M, Wipff J, Ruiz B, Hachulla E, Diot E, 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(8):2472–2479. https://doi.org/10.1002/art.24688 Glas J, Seiderer J, Nagy M, Fries C, Beigel F, Weidinger M, Brand S (2010) Evidence for STAT4 as a common autoimmune gene: rs7574865 is associated with colonic Crohn's disease and early disease onset. PLoS One 5(4):e10373. https://doi.org/10.1371/journal.pone.0010373 Zervou MI, Sidiropoulos P, Petraki E, Vazgiourakis V, Krasoudaki E, Raptopoulou A, 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(9):567–571. https://doi.org/10.1016/j.humimm.2008.06.006 Ramírez OB, Rincón JM, Cobos RB, Ávila IA, Bello JR (2016) STAT4 confers risk for rheumatoid arthritis and systemic lupus erythematosus in Mexican patients. Immunol Lett 175:40–43. https://doi.org/10.1016/j.imlet.2016.05.003 Kiyohara C, Washio M, Horiuchi T, Tada Y, Asami T, Ide S, Takahashi H (2009) Cigarette smoking, STAT4 and TNFRSF1B polymorphisms, and systemic lupus erythematosus in a Japanese population. J Rheumatol 36(10):2195–2203. https://doi.org/10.3899/jrheum.090181 Li C, Zhao L, Wang W, Li H, Meng X, Chen S (2015) STAT4 rs7574865 polymorphism contributes to the risk of type 1 diabetes: a Meta analysis. Int J Clin Exp Med 8(2):2471–2475 El-Lebedy D, Raslan H, Ibrahim A, Ashmawy I, Abd El-Aziz S, Mohammed AM (2017) Association of STAT4 rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoid arthritis and non-systemically reacting antibodies in Egyptian patients. Clin Rheumatol 36(9):1981–1987. https://doi.org/10.1007/s10067-017-3632-7 Liang YL, Wu H, Shen X, Li PQ, Yang XQ, Liang L, Tian WH, Zhang LF, Xie XD (2012) Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis. Mol Biol Rep 39(9):8873–8882. https://doi.org/10.1007/s11033-012-1754-1 Yuan H, Feng JB, Pan HF, Qiu LX, Li LH, Zhang N, Ye DQ (2010) A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Mod Rheumatol 20(3):257–262. https://doi.org/10.1007/s10165-010-0275-9 Yi J, Fang X, Wan Y, Wei J, Huang J (2015) STAT4 polymorphisms and diabetes risk: a meta-analysis with 18931 patients and 23833 controls. Int J Clin Exp Med 8(3):3566–3572 Fichna M, Żurawek M, Bogusz-Górna K, Małecki PP, Niechciał E, Sidoruk A, Furman K, Fichna P (2020) STAT4 sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children. Cent Eur J Immunol 45(1):22–28. https://doi.org/10.5114/ceji.2019.92492 Park Y, Lee HS, Park Y, Min D, Yang S, Kim D, Cho B (2011) Evidence for the role of STAT4 as a general autoimmunity locus in the Korean population. Diabetes Metab Res Rev 27(8):867–871. https://doi.org/10.1002/dmrr.1263 de Azevêdo Silva, J., Tavares, N. A. C., Santos, M. M. S., Moura, R., Guimarães, R. L., Araújo, J., Crovella S & Brandão, L. A. C. (2015). Meta-analysis of STAT4 and IFIH1 polymorphisms in type 1 diabetes mellitus patients with autoimmune polyglandular syndrome type III. Zervou MI, Mamoulakis D, Panierakis C, Boumpas DT, Goulielmos GN (2008) STAT4: a risk factor for type 1 diabetes? Hum Immunol 69(10):647–650. https://doi.org/10.1016/j.humimm.2008.07.004