Association of rs1946518 C/A Polymorphism in Promoter Region of Interleukin 18 Gene and Breast Cancer Risk in Iranian Women: A Case-control Study
Breast cancer (BC) is the most frequently diagnosed cancer among women in the world. Genetic polymorphisms in Interleukin (IL) genes are one of the most important risk factors in BC. The aim of this study was to investigate the association of rs1946518 C/A polymorphism in the promoter region of the IL-18 gene and BC risk in Iranian women. In this case-control study, we recruited 140 women with BC as a case group and 140 age and ethnically matched women as healthy controls from East Azerbaijan, Tabriz in Iran. The genomic DNA was extracted using a salting-out method from peripheral blood leukocytes. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotype distribution in BC patients was 37.86% CC, 47.14% CA, and 15.00% AA, whereas in healthy controls these were 40.72% CC, 42.85% CA, and 16.43% AA. Statistical analysis showed that the genotype and allele frequencies of IL-18 rs1946518 C/A polymorphism were not significantly different between BC patients and healthy controls (p>0.05). The only significant difference between cases and controls was related to family history (p=0.023). In conclusion, our study indicated that IL-18 rs1946518 C/A polymorphism was not associated with BC in the Iranian women population. However, more studies on different races and geographic areas are required to determine the exact role of rs1946518 C/A polymorphism in prognosis, diagnosis, and risk of BC.
2. DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017; 67(6):439-48.
3. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343(2):78-85.
4. Soheilyfar S, Velashjerdi Z, Hajizadeh YS, Maroufi NF, Amini Z, Khorrami A, et al. In vivo and in vitro impact of miR-31 and miR-143 on the suppression of metastasis and invasion in breast cancer. JBUON 2018; 23(5):1290-6.
5. Fathi Maroufi N, Gholampour Matin M, Ghanbari N, Khorrami A, Amini Z, Haj Azimian S, et al. Influence of single nucleotide polymorphism in IL-27 and IL-33 genes on breast cancer. Br J Biomed Sci 2018; 76(2):1-3.
6. Hamed EA, Zakhary MM, Maximous DW. Apoptosis, angiogenesis, inflammation, and oxidative stress: basic interactions in patients with early and metastatic breast cancer. J Cancer Res Clin Oncol 2012; 138(6):999-1009.
7. Chang JT, Segal BM, Nakanishi K, Okamura H, Shevach EM. The costimulatory effect of IL‐18 on the induction of antigen‐specific IFN‐γ production by resting T cells is IL‐12 dependent and is mediated by up‐regulation of the IL‐12 receptor β2 subunit. Eur J Immunol 2000; 30(4):1113-9.
8. Srivastava S, Salim N, Robertson M. Interleukin-18: biology and role in the immunotherapy of cancer. Curr Med Chem 2010; 17(29):3353-7.
9. Yang Y-C, Chang T-Y, Chen T-C, Chang S-C, Lin W-S, Lee Y-J. Genetic variants in interleukin-18 gene and risk for cervical squamous cell carcinoma. Hum Immunol 2013; 74(7):882-7.
10. Jung MY, Kim SH, Cho D, Kim TS. Analysis of the expression profiles of cytokines and cytokine-related genes during the progression of breast cancer growth in mice. Oncol Rep 2009; 22(5):1141-7.
11. Eissa S, Zaki SA, El-Maghraby SM, Kadry DY. Importance of serum IL-18 and RANTES as markers for breast carcinoma progression. J Egypt Natl Canc Inst. 2005; 17(1):51-5.
12. Park S, Cheon S, Cho D. The dual effects of interleukin-18 in tumor progression. Cell Mol Immunol 2007; 4(5):329-35.
13. Bao J, Lu Y, Deng Y, Rong C, Liu Y, Huang X, Song L, Li S, Qin X. Association between IL-18 polymorphisms, serum levels, and HBV-related hepatocellular carcinoma in a Chinese population: a retrospective case-control study. Cancer Cell Int 2015; 15(1):72.
14. Giedraitis V, He B, Huang W-X, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol 2001; 112(1-2):146-52.
15. He Y, Sun S, Liu Y, Tian K. Association of IL-8 genetic polymorphisms and breast cancer risk in a Chinese population. Biomed Res 2017; 28(18):7892-8.
16. Huang Q, Qian X, Fan J, Lv Z, Zhang X, Han J, et al. IL-17 promotes angiogenic factors IL-6, IL-8, and Vegf production via Stat1 in lung adenocarcinoma. Sci Rep 2016; 6:36551.
17. Chechlinska M, Kowalewska M, Nowak R. Systemic inflammation as a confounding factor in cancer biomarker discovery and validation. Nat Rev Cancer 2010; 10(1):2-3.
18. Andersen SW, Trentham-Dietz A, Gangnon R, Hampton J, Figueroa J, Skinner H, et al. Breast cancer susceptibility loci in association with age at menarche, age at natural menopause and the reproductive
lifespan. Cancer Epidemiol Biomarkers Prev 2013; 22(3):471–8.
19. Diekstra MH, Liu X, Swen JJ, Boven E, Castellano D, Gelderblom H, et al. Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma. Eur J Clin Pharmacol 2015; 71(12):1477-84.
20. Kassim SK, El-Salahy EM, Fayed ST, Helal SA, Helal T, Azzam EE-d, et al. Vascular endothelial growth factor and interleukin-8 are associated with poor prognosis in epithelial ovarian cancer patients. Clin Biochem 2004; 37(5):363-9.
21. Srabović N, Mujagić Z, Mujanović-Mustedanagić J, Muminović Z, Čičkušić E. Interleukin 18 expression in the primary breast cancer tumour tissue. Med Glas Ljek komore Zenicko doboj kantona 2011; 8(1):109-12.
22. Sözen S, Coskun U, Sancak B, Bukan N, Günel N, Tunc L, et al. Serum levels of interleukin-18 and nitrite+ nitrate in renal cell carcinoma patients with different tumor stage and grade. Neoplasma 2004; 51(1):25-9.
23. Bushley AW, Ferrell R, McDuffie K, Terada KY, Carney ME, Thompson PJ, et al. Polymorphisms of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and IL-18 and the risk of ovarian cancer. Gynecol Oncol 2004; 95(3):672-9.
24. Guo X-G, Xia Y. The Interleukin-18 promoter-607C> A polymorphism contributes to nasopharyngeal carcinoma risk: evidence from a meta-analysis including 1,886 subjects. Asian Pac J Cancer Prev 2013; 14(12):7577-81.
25. Nikiteas N, Yannopoulos A, Chatzitheofylaktou A, Tsigris C. Heterozygosity for interleukin-18-607 A/C polymorphism is associated with risk for colorectal cancer. Anticancer Res 2007; 27(6B):3849-53.
26. Liang T-J, Ma H, Wang C-X, Liu Y-R, Wang X-G. The-137G> C polymorphism in interleukin-18 promoter region and cancer risk: evidence from a meta-analysis of 21 studies. Tumour Biol 2013; 34(6):3483-90.
27. Hajilooi M, Abasi M, Bazmani A, Ahmadi A, Matini M, Solgi G, et al. Evaluation of interleukin-8-251 T/A polymorphisms in visceral leishmaniasis. J Res Health Sci 2014; 15(1):59-61.
28. Soheilyfar S, Nikyar T, Fathi Maroufi N, Mohebi Chamkhorami F, Amini Z, Ahmadi M, et al. Association of IL-10, IL-18, and IL-33 genetic polymorphisms with recurrent pregnancy loss risk in Iranian women. Gynecol Endocrinol 2019; 35(4):342-5.
29. Li X, Ren D, Li Y, Xu J, Liu C, Zhao Y. Increased cancer risk associated with the -607C/A poly-morphism in interleukin-18 gene promoter: an updated meta-analysis including 12,502 subjects. JBUON 2015; 20(3):902-17.
30. Back LdC, Farias T, Da Cunha P, Muniz Y, Ribeiro M, Fernandes B, et al. Functional polymorphisms of interleukin‐18 gene and risk of breast cancer in a Brazilian population. Tissue Antigens 2014; 84(2):229-33.
31. Khalili-Azad T, Razmkhah M, Ghiam A, Doroudchi M, Talei A, Mojtahedi Z, et al. Association of interleukin-18 gene promoter polymorphisms with breast cancer. Neoplasma 2009; 56(1):22-5.
32. Taheri M, Hashemi M, Eskandari-Nasab E, Fazaeli A, Arababi F, Bahrani-Zeidabadi M, et al. Association of-607 C/A polymorphism of IL-18 gene (rs1946518) with breast cancer risk in Zahedan, Southeast Iran. Prague Med Rep 2012; 113(3):217-22.
33. Hasan F, Naif H. Association of Gene Polymorphisms and Serum Levels of IL-18 with the Susceptibility to Infection with Hepatitis B Virus. J Infect Dis Med 2017; 2(3):117-25.
34. Bao J, Lu Y, Deng Y, Rong C, Liu Y, Huang X, et al. Association between IL-18 polymorphisms, serum levels, and HBV-related hepatocellular carcinoma in a Chinese population: a retrospective case–control study. Cancer Cell Int 2015; 15(1):72-80.
35. Zhao Y, Wang S, Zhang Z, Qin C, Yang X, Xie Q. Association of IL-18 genetic polymorphisms and haplotypes with breast cancer risk in a Chinese population. Biomed Res 2017; 28(19):8433-7.
36. Isazadeh A, Azimian SH, Tariverdi N, Rahmani SA, Esmaeili M, Karimkhanilouei S, et al. Effects of coagulation factor XIII (Val34Leu) polymorphism on recurrent pregnancy loss in Iranian Azeri women. LaboratoriumsMedizin-J Lab Med 2017; 41(2):89-92.
37. Isazadeh A, Hajazimian S, Rahmani SA, Mohammadoo-Khorasani M, Samanmanesh S, Karimkhanilouei S. The effects of Factor II (rs1799963) polymorphism on recurrent pregnancy loss in Iranian Azeri women. La Rivista Italiana della Medicina di Laboratorio-Ital J Lab Med 2017; 13(1):37-40.
38. Isazadeh A, Hajazimian S, Rahmani SA, Mohammadoo-Khorasani M, Moghtaran N, Maroufi NF. The effect of factor-xi (rs3756008) polymorphism on recurrent pregnancy loss in Iranian Azeri women. Gene Cell Tissue 2017; 4(1):e43717.