VARIANTS OF С-572G OF IL6 AND С-1112T OF IL13 GENES POLYMORPHISMS AND FEATURES OF THE CLINICAL COURSE OF DIFFUSE TOXIC GOITER

Relevance. Diffuse toxic goiter (DTG) is an autoimmune thyroid disease, which is based on the excessive secretion of autoantibodies to thyroid-stimulating hormone receptor (TRAb). Over the last decades, high relapse rate of thyrotoxicosis is observed after withdrawal of conservative therapy. At the same time, there are no reliable criteria to predict the efficiency of drug therapy. It is widely discussedin literature that singlenucleotide polymorphism (SNP) at cytokine-encoding genesnot only confers susceptibility to the DTG, but also has impact on the features ofclinical course of the disease .

The aim of this study was to determine whether the SNPs in -572C/G (rs1800796) of IL6 or -1112C/Т (rs1800925) of IL13 genes can influence thedevelopment and clinical course of the diffuse toxic goiter (DTG).

Materials and methods. We examined 270 patients with diffuse toxic goiter and 200 healthy persons (reference subjects)with the help of molecular genetic analysis of polymorphic variants of the gene encoding the Pro-inflammatory cytokines. Identification of C-572G of IL6 gene and C-1112T of IL13gene was performed using the PCR method followed by the restriction analysis.

Results. We determined that the carriage of -572G allele of the rs1800796 in IL6 gene isassociated with the growth of recurrence risk of thyrotoxicosis and the absence of remission of DTGin 1.3 times (р=0.031, OR=1.3, 95 %, CI 0.98–1.76) and the carriage of CC genotype of the rs1800925 in IL13 – in 2.3 times (р=0.026, OR=2.3, 95 %, CI 1.09–4.82) respectively. The obtained results allowed to revealnew genetic markers of an adverse course in patients with diffuse toxic goiter, Saint Petersburg residents.

1. Vitti P., Rago T., Chiovato L., et al. Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment. Thyroid. 1997; (7):369–375.

2. Benker G., Reinwein D., Kahaly G., et al. Is there a methimazole dose effect on remission rate in Graves’ disease? Results from a long-term prospective study. The European Multicentre Trial Group of the Treatment of Hyperthyroidism with Antithyroid Drugs. Clinical Endocrinology (Oxf). 1998; 49:451–457.

3. Hedley A.J., Young R.E., Jones S.J., et al. Antithyroid drugs in the treatment of hyperthyroidism of Graves’ disease: long-term follow-up of 434 patients. Scottish Automated Follow-up Register Group. Clinical Endocrinology (Oxf). 1989;31: 209–218

4. Komiya I., Yamada T., Sato A., et al. Remission and recurrence of hyperthyroid Graves’ disease during and after methimazole treatment when assessed by IgE and interleukin 13. Journal of Clinical Endocrinology and Metabolism. 2001; 86:3540-3544

5. Nanba T., Watanabe M., Inoue N., Iwatani Y. Increases of the Th1/Th2 cell ratio in severe Hashimoto’s disease and in the proportion of Th17 cells in intractable Graves’ disease. Thyroid 2009, 19(5):495–501.

6. Kocjan T., Wraber B., Repnik U., Hojker S. Changes in Th1/Th2 cytokine balance in Graves’ disease. Pflugers Arch. 2000;440: 94-95

7. Li C., Yuan J., Zhu Y., Yang X., et al. Imbalance of Th17/Treg in Different Subtypes of Autoimmune Thyroid Diseases. Cellular Physiology and Biochemistry. 2016;(40):245-252

8. Khan F.A., Al-Jameil N., Khan M.F., Al-Rashid M., Tabassum H. Thyroid dysfunction: an autoimmune aspect. International Journal of Clinical and Experimental Medicine. 2015;8(5):6677-6681

9. Kristensen B. Regulatory B and T cell responses in patients with autoimmune thyroid disease and healthy controls. Danish Medical Journal. 2016 Feb;63(2)

10. Salvi M., Pedrazzoni M., Girasole G. et al. Serum concentrations of proinflammatory cytokines in Graves’ disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking. European Journal of Endocrinology. 2000;(143):

11. 97-202

12. Zhu W., Liu N., Zhao Y., Jia H., Cui B., Ning G. Association analysis of polymorphisms in IL-3, IL-4, IL-5, IL-9, and IL-13 with Graves’ disease. Journal of Endocrinological Investigation. 2010;33(10):751-755.

13. Inoue N., Watanabe M., Nakaguchi A., Ueda D. et al. Functional polymorphisms affecting Th1 differentiation are associated with the severity of autoimmune thyroid diseases. Endocrine Journal. 2017.

14. Niyazoglu M., Baykara O., Koc A. et al. Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1β and TNF-α with Graves Disease and Graves Ophthalmopathy. Gene. 2014; 547(2): 226-232

15. Inoue N., Watanabe M., Morita M., et al. Association of functional polymorphisms in promoter regions of IL5, IL6 and IL13 genes with development and prognosis of autoimmune thyroid diseases. Clinical and Experimental Immunology. 2011;163(3):318-323.

16. Bednarczuk T., Placha G., Jazdzewski K. et al. Interleukin-13 gene polymorphisms in patients with Graves’ disease. Clinical Endocrinology (Oxf). 2003;59(4):519-525.

17. Simmonds M.J., Heward J.M., Franklyn J.A., Gough S.C. IL-13 and chromosome 5q31- q33: problems of identifying association within regions of linkage to Graves’ disease. Clinical Endocrinology (Oxf). 2005; 63:695–697

18. Hiromatsu Y., Fukutani T., Ichimura M. et al. Interleukin-13 gene polymorphisms confer the susceptibility of Japanese populations to Graves’ disease. Journal of Clinical Endocrinology and Metabolism. 2005;90(1):296-301.

19. Blin N., Stafford D.W. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976;3(9):2303-2308

20. Mikos H., Mikos M., Obara-Moszynska M., Niedziela M. The role of the immune system and cytokines involved in the pathogenesis of autoimmune thyroid disease. Endokrynologia Polska. 2014;65(2):150-155

21. McKenzie AN. Regulation of T helper type 2 cell immunity by interleukin-4 and interleukin-13. Pharmacology & Therapeutics. 2000;88(2):143-151