POLYMORPHISM OF THE GENES OF INFLAMMATORY CYTOKINES IL6 AND IL1B IN PATIENTS WITH GASTRIC CANCER IN A CLINICAL CASE-CONTROL STUDY

Background: Genetic polymorphism of some inflammatory cytokines is associated with the risk of developing specific, H. pylori-associated diseases, including gastric cancer (GC). Aim: To study the genotypes and alleles frequencies of polymorphism 174G / C (rs1800795) of the IL6 gene and polymorphism -511C / T (rs16944) of the IL1B gene, as well as their association with biomarkers of atrophy in patients with GC in the clinical «case-control» study. Materials and methods: 80 patients with GC (45 mails and 35 females with an average age of 61.0 ± 13.4 years) from two medical centers were studied. In the control, DNA samples from 87 subjects were matched by sex and age from the base of the multicenter cohort study HAPIEE. DNA was isolated from venous blood using phenol-chloroform extraction. DNA samples were genotyped according to published methods. Serum samples were tested using a diagnostic kit for enzyme-linked immunosorbent assays to determine the levels of pepsinogen I (PGI), PGII, PGI/PGII ratios, gastrin-17 and IgG antibodies to H. pylori. Results: In the general group, association of polymorphisms of 174 G/C of the IL6 gene and the -511C/T gene of the IL1B gene with the GC was not found. However, in women, the frequency of the G/G genotype of the IL6 gene was 2 times higher in the group with G/C than in the control (p=0.03). In patients with corpus atrophy, the G/G genotype was revealed twice as often as homozygous C/C variant of the IL6 gene (p=0.002). In patients with GC, the genotype with a rare T allele (C/T + T/T) of the IL1B gene was significantly more frequent than the common homozygous C/C variant (p=0.03). The rare homozygous T/T genotype was significantly less frequent in patients with GC and no signs of corpus atrophy (PGI >30 μg/l): 11.3% vs 47.2% (C/T genotype) and vs 41.5% (genotype C/C) (p <0.001). Conclusions: The received data allow assuming the possible connection of studied polymorphisms with the formation of a cancer phenotype of the gastritis, which requires further study of their significance (weight) in the GC riskometry.

rs1800795, rs16944, IL6, IL1В, H.pylori, gastric cancer, polymorphism, rs1800795, rs16944, IL6, IL1B, pepsinogenes

1. Crew K. D., Neugut A. I. Epidemiology of gastric cancer. World J Gastroenterol, 2006, vol. 12(3), pp. 354-362.

2. Jemal A., Thomas A., Murray T., Thun M. Cancer statistics, 2002. CA Cancer J Clin, 2002, vol. 52, pp. 23-47.

3. Давыдова М. И., Аксель Е. М. Статистика злокачественных новообразований в России и странах СНГ в 2012 году. Москва, 2014. 226 с.

4. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res, 1992, vol. 52(24), pp. 6735-40.

5. Schlemper R. J., Riddell R. H., Kato Y., Borchard F. et al. The Vienna classifcation of gastrointestinal epithelial neoplasia. Gut, 2000, vol. 47(2), pp. 251-5.

6. Parkin D. M. International variation. Oncogene, 2004, vol. 23, pp. 6329-40.

7. Agréus L., Kuipers E.J, Kupcinskas L., Malfertheiner P. et al. Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol, 2012, vol. 47(2), pp. 136-147.

8. Miki K. Gastric cancer screening using the serum pepsinogen test method. Gastric Cancer, 2006, vol.9, pp. 245-253.

9. Yamaoka Y., Kita M., Kodama T., Sawai N., Imanishi J. Helicobacter pylori cagA gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology, 1996, vol. 110, pp. 1744-52.

10. McColl K.E., El-Omar E., Gillen D. Helicobacter pylori gastritis and gastric physiology. Gastroenterol Clin North Am, 2000, vol. 29, pp. 687-703.

11. Lowry S. F. Cytokine mediators of immunity and inflammation. Arch Surg, 1993, vol. 128, pp. 1235-1241.

12. Romano M., Sironi M., Toniatti C., Polentarutti N. et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity.1997, vol. 6, pp. 315-325.

13. Chi L. J., Lu H. T., Li G. L., Wang X. M. et al. Involvement of T helper type 17 and regulatory T cell activity in tumour immunology of bladder carcinoma. Clin Exp Immunol, 2010, vol. 161, pp. 480-489.

14. Ray A., LaForge K.S. and Sehgal P. B. On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. Mol Cell Biol, 1990, vol. 10, pp. 5736-5746.

15. Du Y., Gao L., Zhang K., Wang J. Association of the IL6 polymorphism rs1800796 with cancer risk: a meta-analysis. Genetics and Molecular Research, 2015, vol. 14(4), pp. 13236-13246.

16. Juni W., Wenjun H., Jinxin L., Legen N. et al. Association of IL-6 polymorphisms with gastric cancer risk: evidences from a meta-analysis. Cytokine, 2012, vol. 59(1), pp. 176-83.

17. Маев И. В., Кучерявый Ю. А., Оганесян Т. С. Аллельный полиморфизм интерлейкина-1β при геликобактериозе. Российский журнал гастроэнтерологии, гепатологии и колопроктологии. 2008, № 8, c. 4-11.

18. Schepp W., Dehne K., Herrmuth H. et al. Identification and functional importance of IL-1 receptors on rat parietal cells. Am J Physiol, 1998, vol. 275, pp. 1094-1105.

19. Hitzler I., Sayi A., Kohler E., Engler D. B. et al. Caspase-1 has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1β and IL-18. J Immunol, 2012, vol. 188(8), pp. 3594-3602.

20. Berezhnaya N. M. The role of immune cells in the tumor microenvironment: The interaction of cells of the immune system with the other components of the microenvironment. Oncology 2009; 11 (2): 86-93.

21. Macri A., Versaci A., Loddo S., Scuderi G. et al. Serum levels of interleukin-1 beta, interleukin-8 and tumor necrosis factor alpha as markers of gastric cancer. Biomarcers, 2006, vol. 11(2), pp. 184-193.

22. Gonzalez C.A, Sala N, Capella G. Genetic susceptibility and gastric cancer risk. Int J Cancer, 2004, vol. 100, pp. 249-260.

23. El-Omar E.M., Carrington M., Chow W. H. et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature, 2000, vol. 404, pp. 398-402.

24. Jyh-Ming Liou et al. IL-1β-511 polymorphism is associated with increased host susceptibility to Helicobacter pylori infection in Chinese. Helicobacter, 2007, vol. 12, pp. 142-149.

25. Machado J. C., Pharoah P., Sousa S. Interleukin-1β and interleukin-1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology, 2001, vol. 121(4), pp. 823-829.

26. Rad R., Dossumbekova A., Neu B. et al. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut, 2004, vol. 53, pp. 1082-1089.

27. Farin Kamangar et al. Polymorphisms in inflammation related genes and risk of gastric cancer (Finland). Cancer Causes Control, 2006, vol. 17, pp. 117-125.

28. Matsukura N., Yamada S., Kato S. et al. Genetic differences in interleukin-1β polymorphisms among four Asian populations: an analysis of the Asian paradox between H. pylori infection and gastric cancer incidence. J Exp Clin Cancer Res, 2003, vol. 22, pp. 47-55.

29. Manniatis T, Fritsch E.F, Sambrook J. Molecular cloning: A laboratory manual. Cold spring harbor, New York, 1982.

30. Zhang D. et al. Association of IL-1beta gene polymorphism with cachexia from locally advanced gastric cancer. BMC Cancer, 2007, vol. 7, pp. 45.

31. Bartchewsky W. Jr., Martini M. R., Masiero M., Squassoni A. C., Alvarez M. C., Ladeira M. S., Salvatore D., Trevisan M., Pedrazzoli J. Jr. Effect of Helicobacter pylori infection on IL-8, IL-1beta and COX- 2 expression in patients with chronic gastritis and gastric cancer. Scand J Gastroenterol, 2009, vol. 44 (2), pp. 153-161.

32. Bennermo M., Held C., Stemme S., Ericsson C. G. et al. Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases? Clin Chem, 2004, vol. 50(11), pp. 2136-40.

33. Hwang I. R., Hsu P. I., Peterson L. E., Gutierrez O. et al. Interleukin-6 genetic polymorphisms are not related to Helicobacter pylori associated gastroduodenal diseases. Helicobacter, 2003, vol. 8, pp. 142-8.

34. Pohjanen V. M., Koivurova O. P., Mäkinen J. M., Karhukorpi J. M. et al. Interleukin 6 gene polymorphism -174 is associated with the diffuse type gastric carcinoma, 2013, vol. 52(10), pp. 976-82.

35. He C, Tu H, Sun L. et al. Helicobacter pylori-related host gene polymorphisms associated with susceptibility of gastric carcinogenesis: a two-stage case-control study in Chinese. Carcinogenesis, 2013, vol. 34, pp. 1450-7.

36. El-Omar E.M, Carrington M., Chow W. H., McColl K.E. et al. The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer. Nature, 2001, vol. 5, pp. 6842-99.

37. Kyoto global consensus report on Helicobacter pylori gastritis. Gut, 2015, vol. 64 (9), pp.1353-1367.