The polymorphism of IL18RAP and IL18R1 genes associated with risks of the development of myocardial infarction in patients with stable coronary artery disease

Objective: to assess the probability of pathogenic effects OF Il-18 (IL18, IL18R1 and IL18RAP) gene polymorphism on the risk of myocardial infarction in patients with stable coronary heart disease.

Materials and methods: the present study was performed with the inclusion of 260 patients with stable coronary heart disease (CHD), residents of the industrial region of Western Siberia. Molecular genetic testing was performed on nine polymorphic sites of il18, IL18R1, IL18RAP genes.

Results: associations of polymorphic sites rs13015714 IL18R1 and rs917997 IL18RAP with risks of myocardial infarction were Determined (OR =1.95 (95% CI =1.06-3.58), p =0.029 and OR =2.01 (95% CI =1.11-3.64), p=0.018).

Conclusion: to confirm the role of polymorphism IL18, IL18R1, IL18RAP in the pathogenesis of atherosclerosis, prospective monitoring of this group of patients is necessary to identify cases of manifestation of clinical signs in persons with adverse prognosis.

1. Godefroy T, Lubos E, Nicaud V, et al. Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. AtheroGene Investigators. Circulation.2005;112(5):643-650.

2. Nakanishi K, Yoshimoto T, Tsutsui H, et al. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev. 2001;12:53-72.

3. Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med. 2002; 195: 245–257.

4. Blankenberg S, Tiret L, Bickel C, et al. Interleukin 18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 2002; 106: 24–30.

5. Blankenberg S, Luc G, Ducimetière P, et al. on behalf of the PRIME Study Group. Interleukin-18 and the risk of coronary heart disease in European men: The Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 2003; 108: 2453–2459.

6. Zykov MV, Kashtalap VV, Bykova I S, et al. Clinical and predictive value of serum interleukine-18 in ST elevation myocardial infarction. Russian Journal of Cardiology. 2015;11(127): 70-74. In Russian

7. Zhu J, Liu C, Teng X, et al. Association of the interleukin-18 receptor 1 and interleukin-18 receptor accessory protein polymorphisms with the risk of esophageal cancer. Biomedical reports. 2016; 4(2): 227-235.

8. Paramel Varghese G, Folkersen L, Strawbridge RJ, et al. NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. J Am Heart Assoc. 2016; 5 (5): e003031.

9. Boraschi D, Dinarello CA. IL-18 in autoimmunity: review. Eur. Cytokine Netw. 2006;17: 224–252.

10. Tiret L, Godefroy T, Lubos E, et al. Atherogene Investigators: Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation. 2005;112:643-650.

11. Grisoni M.-L, Proust C, Alanne M, et al. Project: Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events: The MORGAM Project. Eur J Hum Genet. 2008; 16: 1512-1520.

12. Grisoni M.-L, Proust C, Alanne M, et al. Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project BMC Medical Genetics. 2009;10: 44.

13. Hedl M, Zheng S, Abraham C. The IL18RAP Region Disease Polymorphism Decreases IL-18RAP/IL18R1/IL-1R1 Expression and Signaling through Innate Receptor–Initiated Pathways. J Immunol. 2014;192 (12): 5924-5932.

14. Nolan KF, Greaves DR, Waldmann H. The human interleukin 18 gene IL18 maps to 11q22.2-q22.3, closely linked to the DRD2 gene locus and distinct from mapped IDDM loci. Genomics. 1998; 51: 161-168.

15. Hoseini F, Mahmazi S, Mahmoodi K, et al. Evaluation of the Role of -137G/C Single Nucleotide Polymorphism (rs187238) and Gene Expression Levels of the IL-18 in Patients with Coronary Artery Disease.Oman Med J. 2018;33(2):118-125.

16. Omer W, Naveed AK, Khan OJ, et al. Role of Cytokine Gene Score in Risk Prediction of Premature Coronary Artery Disease. Genet Test Mol Biomarkers. 2016;20(11): 685-691.

17. Koch W, Wolferstetter H, Schatke A, et al. Interleukin 18 gene variation and risk of acute myocardial infarction. Cytokine. 2011; 3:786-791.

18. Kariž S, Petrovič D. Interleukin-18 Promoter Gene Polymorphisms are not associated with Myocardial Infarction in Type 2 Diabetes in Slovenia. Balkan J Med Genet.2011.14(1): 3-9.

19. Wang Y-H, Fu L, Wang B. et al. Genetic variants of interleukin-18 are associated with reduced risk of atrial fibrillation in a population from Northeast China. Gene. 2017; 626: 269-274

20. Lu JX, Lu ZQ, Zhang SL, et al. Correlation between interleukin-18 promoter -607C/A polymorphism and susceptibility to ischemic stroke. Braz J Med Biol Res. 2013;46(6):502-506.

21. Ivanova АА, Maksimov VN, Ivanoshchuk DЕ, et al. Association of the CCR2 gene RS1799864, IL18 gene RS187238, and the NOS3 gene RS1799983 with sudden cardiac death. Forensic medicine journal.2016;3(5):20-25. In Russian.

22. Novembre J, Johnson T, Bryc K, et al. Genes mirror geography within Europe. Nature. 2008;456(7218):98–101.

23. Tabakaev MV, Vlasenko AE, Naumova SA, Artamonova GV. Approaches to the evaluation of the environmental influence on cardiovascular pathology among urban population. Complex Issues of Cardiovascular Diseases. 2015;(4):61-66. In Russian.