Russian Journal of Genetics

, Volume 55, Issue 3, pp 378–387 | Cite as

The Role of Allelic Variants of Several Genes of Cytokines in the Development of Gastric Cancer

  • L. F. YusupovaEmail author
  • A. Kh. NurgalievaEmail author
  • I. R. Gilyazova
  • D. S. Prokofyeva
  • F. R. Munasypov
  • Sh. M. Khusnutdinov
  • R. R. Rakhimov
  • R. R. Abdeev
  • D. D. Sakaeva
  • E. K. Khusnutdinova


Pro- and anti-inflammatory cytokines modulate the inflammatory response in the gastric mucosa. The analysis of associations of allelic variants of cytokine genes in the process of tumorous transformation of the gastric mucosa is an urgent problem. Its solution could make it possible to identify the features of production of inflammatory mediators by the immunocompetent cells during gastric carcinogenesis. The frequencies of alleles and genotypes of the rs1143634 and rs16944 loci of the IL1β gene, rs71941886 of the IL1RN gene, rs4073 of the IL8 gene, and rs1800872 of the IL10 gene were analyzed in 221 patients with established diagnosis of gastric cancer, as well as in 279 unrelated healthy individuals from the Republic of Bashkortostan. We discovered an association of the allele С and genotype C/C of the rs1143634 locus of the IL1β gene with a risk of development of malignant tumors of the stomach in men. We identified statistically significant differences in between patients and the control group in the distribution of frequencies of alleles and genotypes of the polymorphic variants: rs16944 of the IL1β gene and rs1800872 of the IL10 gene. Dependence of the associations with clinical features of the disease was also shown. Application of the APSampler algorithm revealed the combinations of alleles and genotypes associated with reduced and increased risk of the development of gastric cancer. The most significant were IL1β (rs1143634)*T + IL1β (rs16944)*T/T, IL8*A + IL10*A + IL1β (rs1143634)*T + IL1β (rs16944)*T, and IL10*A + IL1RN*2/2. The obtained results confirm the influence of the investigated allelic variants of cytokine genes on the risk of developing gastric cancer and play an important role in understanding the genetic structure of the studied pathology.


gastric cancer cytokines association allele polymorphic variant 



The study was supported by the Russian Foundation for Basic Research (grant №17-44-020497 р_а) and the Federal Agency for Scientific Organizations program for support the bioresource collections.


Conflict of interests. The authors declare that they have no conflict of interest.

Statement of compliance with standards of research involving humans as subjects. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants involved in the study.


  1. 1.
    Ferlay, J., Soerjomataram, I., Dikshit, R., et al., Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012, Int. J. Cancer, 2015, vol. 136, no. 5, pp. 359—386. CrossRefGoogle Scholar
  2. 2.
    Kaprin, A.D., Starinskii, V.V., and Petrova, G.V., Zlokachestvennye novoobrazovaniya v Rossii v 2016 godu (zabolevaemost’ i smertnost’) (Malignant Neoplasms in Russia 2016 (Morbidity and Mortality)), Moscow: Moskovskii Nauchno-Issledovatel’skii Onkologicheskii Institut Imeni P.A. Gertsena, 2018.Google Scholar
  3. 3.
    Imyanitov, E.N., Epidemiology and biology of gastric cancer, Prakt. Onkol., 2009, vol. 10, no. 1, pp. 1—7.Google Scholar
  4. 4.
    Baniak, N., Senger, J.L., Ahmed, S., et al., Gastric biomarkers: a global review, World J. Surg. Oncol., 2016, vol. 14, no. 1, p. 212. CrossRefGoogle Scholar
  5. 5.
    Oliveira, C., Seruca, R., and Carneiro, F., Hereditary gastric cancer, Best Pract. Res. Clin. Gastroenterol., 2009, vol. 23, no. 2, pp. 147—157. CrossRefGoogle Scholar
  6. 6.
    Coussens, L.M. and Werb, Z., Inflammation and cancer, Nature, 2002, vol. 420, no. 6917, pp. 860—867.CrossRefGoogle Scholar
  7. 7.
    Mathew, C.G., The isolation of high molecular weight eukaryotic DNA, Methods Mol. Biol., 1985, vol. 2, pp. 31—34. Google Scholar
  8. 8.
    Schlesselman, J., Case-Control Studies: Design, Conduct, Analysis, New York: Oxford Univ. Press, 1982, pp. 58—96.Google Scholar
  9. 9.
    Abramson, J.H., WINPEPI updated: computer programs for epidemiologists, and their teaching potential, Epidemiol. Perspect. Innovations, 2011, vol. 8, no. 1, pp. 1—9. CrossRefGoogle Scholar
  10. 10.
    Higgins, J.P. and Thompson, S.G., Quantifying heterogeneity in a meta-analysis, Stat. Med., 2002, vol. 21, no. 11, pp. 1539—1558.CrossRefGoogle Scholar
  11. 11.
    Favorov, A.V., Andreewski, T.V., Sudomoina, M.A., et al., A Markov chain Monte Carlo technique for identification of combinations of allelic variants underlying complex diseases in humans, Genetics, 2005, vol. 171, no. 4, pp. 2113—2121.CrossRefGoogle Scholar
  12. 12.
    Gromova, A.Yu. and Simbirtsev, A.S., Polymorphism in human IL-1 gene family, Tsitokiny Vospalenie, 2005, vol. 4, no. 2, pp. 24—35.Google Scholar
  13. 13.
    Markova, S., Nakamura, T., Makimoto, H., et al., IL-1beta genotype-related effect of prednisolone on IL-1beta production in human peripheral blood mononuclear cells under acute inflammation, Biol. Pharm. Bull., 2007, vol. 30, no. 8, pp. 1481—1487.CrossRefGoogle Scholar
  14. 14.
    Witkin, S.S., Gerber, S., and Ledger, W.J., Influence of interleukin-1 receptor antagonist gene polymorphism on disease, Clin. Infect. Dis., 2002, vol. 34, no. 2, pp. 204—209.CrossRefGoogle Scholar
  15. 15.
    Turner, D.M., Williams, D.M., Sankaran, D., et al., An investigation of polymorphism in the interleukin-10 gene promoter, Eur. J. Immunogenet., 1997, vol. 24, no. 1, pp. 1—8.CrossRefGoogle Scholar
  16. 16.
    Rubanovich, A.V. and Khromov-Borisov, N.N., Reproducibility and predictive value of results in the genetics of predispositions, Mol. Med., 2014, no. 2, pp. 8—12.Google Scholar
  17. 17.
    Nurgalieva, A.Kh., Shaymardanova, E.Kh., Khidiyatova, I.M., et al., Association of cytokine gene polymorphisms in peptic ulcer development in the Bashkortostan Republic, Russ. J. Genet., 2014, vol. 50, no. 12, pp. 1316—1325.CrossRefGoogle Scholar
  18. 18.
    Dinarello, C.A., Interleukin-1 in the pathogenesis and treatment of inflammatory diseases, Blood, 2011, vol. 117, no. 14, pp. 3720—3732. CrossRefGoogle Scholar
  19. 19.
    Zhang, Y., Liu, C., Peng, H., et al., IL1 receptor antagonist gene IL1-RN variable number of tandem repeats polymorphism and cancer risk: a literature review and meta-analysis, PLoS One, 2012, vol. 7, no. 9. e46017. CrossRefGoogle Scholar
  20. 20.
    Vincenzi, B., Patti, G., Galluzzo, S., et al., Interleukin 1beta-511T gene (IL1beta) polymorphism is correlated with gastric cancer in the Caucasian population: results from a meta-analysis, Oncol. Rep., 2008, vol. 20, no. 5, pp. 1213—1220.Google Scholar
  21. 21.
    Konenkov, V.I. and Smol’nikova, M.V., Structural bases and functional significance of allelic polymorphism of human cytokine genes and their receptors, Med. Immunol., 2003, vol. 5, nos. 1—2, pp. 11—28.Google Scholar
  22. 22.
    Gabay, C. and Palmer, G., Mutations in the IL1RN locus lead to autoinflammation, Nat. Rev. Rheumatol., 2009, vol. 5, no. 9, pp. 480—482. CrossRefGoogle Scholar
  23. 23.
    Bajnok, E., Takács, I., Vargha, P., et al., Lack of association between interleukin-1 receptor antagonist protein gene polymorphism and bone mineral density in Hungarian postmenopausal women, Bone, 2000, vol. 27, no. 4, pp. 559—562.CrossRefGoogle Scholar
  24. 24.
    Boiardi, L., Salvarani, C., Timms, J.M., et al., Interleukin-1 cluster and tumor necrosis factor-alpha gene polymorphisms in polymyalgia rheumatic, Clin. Exp. Rheumatol., 2000, vol. 18, no. 6, pp. 675—681.Google Scholar
  25. 25.
    Guasch, J.F., Bertina, R.M., and Reitsma, P.H., Five novel intragenic dimorphisms in the human interleukin-1 genes combine to high informativity, Cytokine, 1996, vol. 8, no. 8, pp. 598—602.CrossRefGoogle Scholar
  26. 26.
    Raza, Y., Khan, A., Khan, A.I., et al., Combination of interleukin 1 polymorphism and Helicobacter pylori infection: an increased risk of gastric cancer in Pakistani population, Pathol. Oncol. Res., 2017, vol. 23, no. 4, pp. 873—880. CrossRefGoogle Scholar
  27. 27.
    Xue, H., Lin, B., Ni, P., et al., Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis, J. Gastroenterol. Hepatol., 2010, vol. 25, no. 10, pp. 1604—1617. CrossRefGoogle Scholar
  28. 28.
    Yin, Y.W., Hu, A.M., Sun, Q.Q., et al., Association between interleukin-8 gene -251 T/A polymorphism and the risk of peptic ulcer disease: a meta-analysis, Hum. Immunol., 2013, vol. 74, no. 1, pp. 125—130. CrossRefGoogle Scholar
  29. 29.
    Felipe, A.V., Silva, T.D., Pimenta, C.A., et al., Interleukin-8 gene polymorphism and susceptibility to gastric cancer in a Brazilian population, Biol. Res., 2012, vol. 45, no. 4, pp. 369—374. CrossRefGoogle Scholar
  30. 30.
    Savage, S.A., Hou, L., Lissowska, J., et al., Interleukin-8 polymorphisms are not associated with gastric cancer risk in a Polish population, Cancer Epidemiol. Biomarkers Prev., 2006, vol. 15, no. 3, pp. 589—591.CrossRefGoogle Scholar
  31. 31.
    Ma, J., Wu, D., Hu, X., et al., Associations between cytokine gene polymorphisms and susceptibility to Helicobacter pylori infection and Helicobacter pylori related gastric cancer, peptic ulcer disease: a meta-analysis, PLoS One, 2017, vol. 12, no. 4. e0176463. CrossRefGoogle Scholar
  32. 32.
    Mocellin, S., Marincola, F.M., and Young, H.A., Interleukin-10 and the immune response against cancer: a counterpoint, J. Leukoc. Biol., 2005, vol. 78, no. 5, pp. 1043—1051.CrossRefGoogle Scholar
  33. 33.
    Ding, Q., Shi, Y., Fan, B., et al., The interleukin-10 promoter polymorphism rs1800872 (–592C>A), contributes to cancer susceptibility: meta-analysis of 16 785 cases and 19 713 controls, PLoS One, 2013, vol. 8, no. 2. e57246. CrossRefGoogle Scholar
  34. 34.
    de Oliveira, J.G., Rossi, A.F., Nizato, D.M., et al., Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer, Tumour Biol., 2015, vol. 36, no. 12, pp. 9159—9170. CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  • L. F. Yusupova
    • 1
    Email author
  • A. Kh. Nurgalieva
    • 1
    Email author
  • I. R. Gilyazova
    • 2
  • D. S. Prokofyeva
    • 1
  • F. R. Munasypov
    • 3
  • Sh. M. Khusnutdinov
    • 3
  • R. R. Rakhimov
    • 3
  • R. R. Abdeev
    • 3
  • D. D. Sakaeva
    • 3
  • E. K. Khusnutdinova
    • 1
    • 2
  1. 1.Department of Genetics and Fundamental Medicine, Bashkir State UniversityUfaRussia
  2. 2.Institute of Biochemistry and Genetics, Ufa Federal Research Center, Russian Academy of SciencesUfaRussia
  3. 3.Republican Clinical Oncology CenterUfaRussia

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