Single nucleotide polymorphisms in the STAT3 gene influence AITD susceptibility, thyroid autoantibody levels, and IL6 and IL17 secretion
-
Agnieszka Kotkowska
,
Ewa Sewerynek
Abstract
STAT3 (signal transducer and activator of transcription 3) is an important cellular effector in the Jak/STAT signaling pathway, which plays a pivotal role in human immune system regulation, mediating the effect of different cytokines. In the present study, we assessed the correlation between STAT3 polymorphisms (rs3816769 C>T and rs744166 A>G) and risk of the autoimmune thyroid diseases (AITDs) Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) in the Polish population. Moreover, we evaluated the association of polymorphisms with the thyroid autoantibody levels (TPOAb, TgAb, TRAb) and the correlation between circulating proinflammatory IL6 and IL17 cytokines and thyroid autoantibody levels. The study included 71 AITD patients with HT (n = 39) or GD (n = 32) and a control group (n = 40). DNA SNP genotyping was performed using TaqMan probes. Serum levels of thyroid autoantibodies, IL6 and IL17 were measured according to enhanced chemiluminescence (ECL) assay. Allele A of STAT3 SNP rs744166 A>G was significantly more frequent in both HT and GD patients, while allele G was significantly more frequent in the control group. Similarly, allele C and CC genotype of STAT3 SNP rs3816769 C>T were significantly more frequent in the control group in comparison to HT and GD patients. Significantly higher TgAb median values were associated with CT rs3816769 genotype in HT patients. Serum levels of IL6 and IL17 positively correlated with TPOAb in the HT group. Serum level of IL6 positively correlated with TPOAb in the AITD group. Both studied polymorphisms seem to play a significant role in susceptibility to AITD (HT and GD). STAT3 SNPs may influence TAb level in AITD patients.
References
1. Ivashkiv, L.B. and Hu, X.Y. Signaling by STATs. Arthritis Res. Ther. 6 (2004) 159-168. DOI:10.1186/ar1197.10.1186/ar1197Search in Google Scholar PubMed PubMed Central
2. Wincewicz, A., Moniuszko, T., Sulkowska, M., Rutkowski, R., Koda, M. and Sulkowski, S. Involvement of stat proteins in the pathogenesis of autoimmune diseases. Adv. Clin. Exp. Med. 14 (2005) 785-790.Search in Google Scholar
3. Nishihara, M., Ogura, H., Ueda, N., Tsuruoka, M., Kitabayashi, C., Tsuji, F., Aono, H., Ishihara, K., Huseby, E., Betz, U.A.K., Murakami, M. and Hirano, T. IL-6-gp130-STAT3 in T cells directs the development of IL-17+Th with a minimum effect on that of Treg in the steady state. Int. Immunol. 19 (2007) 695-702. DOI: 10.1093/intimm/dxm045.10.1093/intimm/dxm045Search in Google Scholar PubMed
4. Xiao, L., Muhali, F.S., Cai, T.T., Song, R.H., Hu, R., Shi, X.H., Jiang, W.J., Li, D.F., He, S.T., Xu, J. and Zhang, J.A. Association of single-nucleotide polymorphisms in the STAT3 gene with autoimmune thyroid disease in Chinese individuals. Funct. Integr. Genomics 13 (2013) 455-461. DOI: 10.1007/s10142-013-0337-0.10.1007/s10142-013-0337-0Search in Google Scholar PubMed PubMed Central
5. Cenit, M.C., Alcina, A., Marquez, A., Mendoza, J.L., Diaz-Rubio, M., de las Heras, V., Izquierdo, G., Arroyo, R., Fernandez, O., de la Concha, E.G., Matesanz, F. and Urcelay, E. STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility. Genes Immun. 11 (2010) 264-268. DOI: 10.1038/gene.2010.10.10.1038/gene.2010.10Search in Google Scholar PubMed
6. Sato, K., Shiota, M., Fukuda, S., Iwamoto, E., Machida, H., Inamine, T., Kondo, S., Yanagihara, K., Isomoto, H., Mizuta, Y., Kohno, S. and Tsukamoto, K. Strong evidence of a combination polymorphism of the tyrosine kinase 2 gene and the signal transducer and activator of transcription 3 gene as a DNA-based biomarker for susceptibility to Crohn's disease in the Japanese population. J. Clin. Immunol. 29 (2009) 815-825.DOI: 10.1007/s10875-009-9320-x.10.1007/s10875-009-9320-xSearch in Google Scholar PubMed PubMed Central
7. Ferguson, L.R., Han, D.Y., Fraser, A.G., Huebner, C., Lam, W.J., Morgan, A.R., Duan, H. and Karunasinghe, N. Genetic factors in chronic inflammation: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population. Mutat. Res. Fundam. Mol. Mech. Mutagen. 690 (2010) 108-115. DOI: 10.1016/j.mrfmmm.2010.01.017.10.1016/j.mrfmmm.2010.01.017Search in Google Scholar PubMed
8. Wiebolt, J., Koeleman, B.P.C. and van Haeften, T.W. Endocrine autoimmune disease: genetics become complex. Eur. J. Clin. Invest. 40 (2010) 1144-1155. DOI: 10.1111/j.1365-2362.2010.02366.x.10.1111/j.1365-2362.2010.02366.xSearch in Google Scholar PubMed
9. Simmonds, M.J. GWAS in autoimmune thyroid disease: redefining our understanding of pathogenesis. Nat. Rev. Endocrinol. 9 (2013) 277-287.10.1038/nrendo.2013.56Search in Google Scholar PubMed
10. Pastuszak-Lewandoska, D., Domanska, D., Rudzinska, M., Bossowski, A., Kucharska, A., Sewerynek, E., Czarnecka, K., Migdalska-Sek, M. and Czarnocka, B. CTLA-4 polymorphisms (+49 A/G and-318 C/T) are important genetic determinants of AITD susceptibility and predisposition to high levels of thyroid autoantibodies in Polish children - preliminary study.Acta Biochim. Pol. 60 (2013) 641-646.Search in Google Scholar
11. Kolls, J.K. and Linden, A. Interleukin-17 family members and inflammation. Immunity 21 (2004) 467-476. DOI: 10.1016/j.immuni.2004.08.018.10.1016/j.immuni.2004.08.018Search in Google Scholar PubMed
12. Cenit M.C., Ortego-Centeno, N., Raya, E., Callejas, J.L., Garcia-Hernandez, F.J., Castillo-Palma, J.M., Fernandez-Sueiro, J.L., Magro, C., Solans, R., Castaneda, S., Camps, M., Hidalgo, A., Espinosa, G., Gonzalez-Gay, M.A., Gonzalez-Escribano, M.F. and Javier, M. Influence of the STAT3 genetic variants in the susceptibility to psoriatic arthritis and Behcet's disease. Hum. Immunol. 74 (2013) 230-233. DOI: 10.1016/j.humimm.2012.10.019.10.1016/j.humimm.2012.10.019Search in Google Scholar PubMed
13. Danoy, P., Pryce, K., Hadler, J., Bradbury, L.A., Farrar, C., Pointon, J., Ward, M., Weisman, M., Reveille, J.D., Wordsworth, B.P., Stone, M.A., Maksymowych, W.P., Rahman, P., Gladman, D., Inman, R.D. and Brown, M. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease. PloS Genet. 6 (2010). DOI: 10.1371/journal.pgen.1001195.10.1371/journal.pgen.1001195Search in Google Scholar PubMed PubMed Central
14. Jakkula, E., Leppa, V., Sulonen, A.M, Varilo, T., Kallio, S., Kemppinen, A., Purcell, S., Koivisto, K., Tienari, P., Sumelahti, M.L., Elovaara, I., Pirttila, T., Reunanen, M., Aromaa, A., Oturai, A.B., Sondergaard, H.B., Harbo, H.F., Mero, I.L.,Gabriel, S.B., Mirel, D.B., Hauser, S.L., Kappos, L., Polman, C., De Jager, P.L., Hafler, D.A., Daly, M.J., Palotie, A., Saarela, J. and Peltonen, L. Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene. Am. J. Hum. Genet. 86 (2010) 285-291. DOI: 10.1016/j.ajhg.2010.01.017.10.1016/j.ajhg.2010.01.017Search in Google Scholar PubMed PubMed Central
15. Litonjua, A.A., Tantisira, K.G., Lake, S., Lazarus, R., Richter, B.G., Gabriel, S., Silverman, E.S. and Weiss, S.T. Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma. Respir. Res. 6 (2005) DOI: 10.1186/1465-9921-6-52.10.1186/1465-9921-6-52Search in Google Scholar PubMed PubMed Central
16. Chen, G. and Shannon, M.F. Transcription factors and Th17 cell development in experimental autoimmune encephalomyelitis. Crit. Rev. Immunol. 33 (2013) 165-182.Search in Google Scholar
17. Komiyama, Y., Nakae, S., Matsuki, T., Nambu, A., Ishigame, H., Kakuta, S., Sudo, K. and Iwakura, Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177 (2006) 566-573.Search in Google Scholar
18. Iwakura, Y., Nakae, S., Saijo, S. and Ishigame, H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol. Rev. 226 (2008) 57-79.Search in Google Scholar
19. Afzali, B., Lombardi, G., Lechler, R.I. and Lord, G.M. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin. Exp. Immunol. 148 (2007) 32-46. DOI: 10.1111/j.1365-2249.2007.03356.x.10.1111/j.1365-2249.2007.03356.xSearch in Google Scholar PubMed PubMed Central
20. Ouyang, W., Kolls, J.K. and Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28 (2008) 454-467. DOI: 10.1016/j.immuni.2008.03.004.10.1016/j.immuni.2008.03.004Search in Google Scholar PubMed PubMed Central
21. Harris, T.J., Grosso, J.F., Yen, H.R., Xin, H., Kortylewski, M., Albesiano, E., Hipkiss, E.L., Getnet, D., Goldberg, M.V., Maris, C.H., Housseau, F., Yu, H., Pardoll, B.M. and Drake, C.G. An in vivo requirement for STAT3 signaling in T(H)17 development and T(H)17-dependent autoimmunity(1). J. Immunol. 179 (2007) 4313-4317.Search in Google Scholar
22. Nagafuchi, H., Suzuki, N., Mizushima, Y. and Sakane, T. Constitutive expression of IL-6 receptors and their role in the excessive B-cell function in patients with systemic lupus-erythematosus. J. Immunol. 151 (1993) 6525-6534.Search in Google Scholar
23. Boelen, A., Schiphorst, M.C.P. and Wiersinga, W.M. Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness. J. Clin. Endocrinol. Metab. 77 (1993) 1695-1699. DOI: 10.1210/jc.77.6.1695.10.1210/jc.77.6.1695Search in Google Scholar
24. Diamant, M., Kayser, L., Rasmussen, A.K., Bech, K. and Feldtrassmussen, U. Interleukin-6 production by thyroid epithelial-cells - enhancement by interleukin-1. Autoimmunity 11 (1991) 21-26. DOI: 10.3109/08916939108994704.10.3109/08916939108994704Search in Google Scholar PubMed
25. Weetman, A.P., Brightthomas, R. and Freeman, M. Regulation of interleukin-6 release by human thyrocytes. J. Endocrinol. 127 (1990) 357-361. DOI: 10.1677/joe.0.1270357. 10.1677/joe.0.1270357Search in Google Scholar PubMed
26. Kennedy, R.L., Jones, T.H., Davies, R., Justice, S.K. and Lemoine, N.R. Release of interleukin-6 by human thyroid epithelial-cells immortalized by simian virus-40 DNA transfection. J. Endocrinol. 133 (1992) 477-482. DOI: 10.1677/joe.0.1330477.10.1677/joe.0.1330477Search in Google Scholar PubMed
27. Bartalena, L., Brogioni, S., Grasso, L., Velluzzi, F. and Martino, E. Relationship of the increased serum interleukin-6 concentration to changes of thyroid-function in nonthyroidal illness. J. Endocrinol. Invest. 17 (1994) 269-274. Search in Google Scholar
© 2015 University of Wrocław, Poland
Articles in the same Issue
- Identification of drought-induced transcription factors in Sorghum bicolor using GO term semantic similarity
- Evaluation of the potential of alkylresorcinols as superoxide anion scavengers and sox-regulon modulators using nitroblue tetrazolium and bioluminescent cell-based assays
- Cyclic phosphatidic acid induces G0/G1 arrest, inhibits AKT phosphorylation, and downregulates cyclin D1 expression in colorectal cancer cells
- Polymorphism of the APEX nuclease 1 gene in keratoconus and Fuchs endothelial corneal dystrophy
- FE65: Roles beyond amyloid precursor protein processing
- Single nucleotide polymorphisms in the STAT3 gene influence AITD susceptibility, thyroid autoantibody levels, and IL6 and IL17 secretion
- Antioxidant effect of a fermented powder of Lady Joy bean in primary rat hepatocytes
- Oncogene-dependent survival of highly transformed cancer cells under conditions of extreme centrifugal force – implications for studies on extracellular vesicles
- Changes in cell death of peripheral blood lymphocytes isolated from children with acute lymphoblastic leukemia upon stimulation with 7 Hz, 30 mT pulsed electromagnetic field
- Flow cytometric analysis of apoptosis in cryoconserved chicken primordial germ cells
- GGeneration of an efficient artificial promoter of bovine skeletal muscle alpha-actin gene (ACTA1) through addition of cis-acting element
Articles in the same Issue
- Identification of drought-induced transcription factors in Sorghum bicolor using GO term semantic similarity
- Evaluation of the potential of alkylresorcinols as superoxide anion scavengers and sox-regulon modulators using nitroblue tetrazolium and bioluminescent cell-based assays
- Cyclic phosphatidic acid induces G0/G1 arrest, inhibits AKT phosphorylation, and downregulates cyclin D1 expression in colorectal cancer cells
- Polymorphism of the APEX nuclease 1 gene in keratoconus and Fuchs endothelial corneal dystrophy
- FE65: Roles beyond amyloid precursor protein processing
- Single nucleotide polymorphisms in the STAT3 gene influence AITD susceptibility, thyroid autoantibody levels, and IL6 and IL17 secretion
- Antioxidant effect of a fermented powder of Lady Joy bean in primary rat hepatocytes
- Oncogene-dependent survival of highly transformed cancer cells under conditions of extreme centrifugal force – implications for studies on extracellular vesicles
- Changes in cell death of peripheral blood lymphocytes isolated from children with acute lymphoblastic leukemia upon stimulation with 7 Hz, 30 mT pulsed electromagnetic field
- Flow cytometric analysis of apoptosis in cryoconserved chicken primordial germ cells
- GGeneration of an efficient artificial promoter of bovine skeletal muscle alpha-actin gene (ACTA1) through addition of cis-acting element
