Polymorphisms in F2, F7, and PAI1 genes in men with coronary atherosclerosis

Aim. To study the associations of polymorphisms in F2, F7, and PAI1 genes with the presence of vulnerable plaque in coronary arteries (CA) and the blood concentration of proteins encoded by these genes.

Material and methods. The study included 101 men 40-70 years old with documented coronary atherosclerosis, who underwent coronary artery bypass grafting. According to the histological analysis of atherosclerotic plaques, men were divided into 2 groups: 40 men (39,6%) with stable plaque; 61 men (60,4%) with vulnerable plaques in CA. Genotyping of rs1799963 and rs6046 was performed by reverse transcription polymerase chain reaction, rs1799889 — by polymerase chain reaction. Statistical processing was performed using the SPSS 16.0 software package.

Results. In patients with stable plaques, allele A of rs6046 polymorphism in the F7 gene was observed in 2,9 times more often (95% confidence interval (CI), 1,20-7,20, p=0,021) than in men with vulnerable plaques. The odds ratio of the GA genotype carriage is 4,03 times higher among patients with stable plaques in CA compared with vulnerable plaques (95% CI, 1,49-10,93, p=0,006). The odds ratio of the 5G/4G genotype carriage among patients with stable plaques in CA is 2,47 times higher than in patients with vulnerable plaques (95% CI, 1,08-5,62, p=0,039). The 4G/4G genotype carriage is 5,85 times much more common in men with stable plaques (95% CI, 1,61-21,34, p=0,003).

Conclusion. Polymorphism in the PAI1 (rs1799889) and F7 (rs6046) genes are associated with the presence of vulnerable plaques in CA in men with verified coronary atherosclerosis. There were no differences between the groups in the frequencies of genotypes and alleles of the rs1799963 polymorphism of the F2 gene. Also, no significant differences were found in the blood levels of PAI-1 and factor VII in groups with different genotypes.

1. Kalayi Nia S, Ziaee S, Boroumand MA, et al. The impact of vascular endothelial growth factor +405 C/G polymorphism on long-term outcome and severity of coronary artery disease. J Clin Lab Anal. 2017;31(4):e22066. doi:10.1002/jcla.22066.

2. Abraham G, Havulinna AS, Bhalala OG, et al. Genomic prediction of coronary heart disease. Eur Heart J. 2016;37:3267-78. doi:10.1093/eurheartj/ehw450.

3. de Vries MA, Trompet S, Mooijaart SP, et al. Complement receptor 1 gene polymorphisms are associated with cardiovascular risk. Atherosclerosis. 2017;257:16-21. doi:10.1016/j. atherosclerosis.2016.12.017.

4. Sayın Kocakap DB, Doğru MT, Şimşek V, et al. The association of paraoxonase 1 gene L55M polymorphism with the extent and severity of coronary artery disease in the Turkish population and its dependence on gender. Anatol J Cardiol. 2016;16(3):175-82. doi:10.5152/akd.2015.6010.

5. Li L, Pan Y, Dai L, et al. Association of genetic polymorphisms on vascular endothelial growth factor and its receptor genes with susceptibility to coronary heart disease. Med Sci Monit. 2016;22:31-40. doi:10.12659/MSM.895163.

6. Li JF, Peng DY, Ling M, Yin Y. Evaluation of adenosine triphosphate-binding cassette transporter A1 (ABCA1) R219K and C-reactive protein gene (CRP) +1059G/C gene polymorphisms in susceptibility to coronary heart disease. Med Sci Monit. 2016;22:29993008. doi:10.12659/MSM.897104.

7. Waksman R, Seruys PW. Handbook of the Vulnerable Plaque. London, 2004. p. 48. ISBN: 0-203-48989-6.

8. Bochenek ML, Schutz E, Schafer K. Endothelial cell senescence and thrombosis: ageing clots. Thrombosis research. 2016;147:36-45. doi:10.1016/j.thromres.2016.09.019.

9. Yuan HQ, Hao YM, Ren Z, et al. Tissue factor pathway inhibitor in atherosclerosis. Clin Chim Acta. 2019;491:97-102. doi:10.1016/j.cca.2019.01.024.

10. Cimmino G, Ciccarelli G, Golino P. Role of Tissue Factor in the Coagulation Network. Semin Thromb Hemost. 2015;41(7):708-17. doi:10.1055/s-0035-1564045.

11. Martinelli N, Girelli D, Baroni M, et al. Activated factor VII-antithrombin complex predicts mortality in patients with stable coronary artery disease: a cohort study. J Thromb Haemost. 2016;14(4):655-66. doi:10.1111/jth.13274.

12. Green D, Foiles N, Chan C, et al. An association between clotting factor VII and carotid intima-media thickness: the CARDIA study. Stroke. 2010;41(7):1417-22. doi:10.1161/STROKEAHA.110.580100.

13. DB Gene. F7 coagulation factor VII [Homo sapiens (human)] — NCBI. (n.d.). Retrieved September 07, 2020, from https://www.ncbi.nlm.nih.gov/gene/2155.

14. Huang H, Long W, Zhao W, et al. Polymorphism of R353Q (rs6046) in factor VII and the risk of myocardial infarction: A systematic review and meta-analysis. Medicine (Baltimore). 2018;97(39):e12566. doi:10.1097/MD.0000000000012566.

15. Olson NC, Raffield LM, Lange LA, et al. Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk. J Thromb Haemost. 2018;16(1):19-30. doi:10.1111/jth.13899.

16. Mo X, Hao Y, Yang X, et al. Association between polymorphisms in the coagulation factor VII gene and coronary heart disease risk in different ethnicities: a meta-analysis. BMC Med Genet. 2011;12:107. doi:10.1186/1471-2350-12-107.

17. Zakai NA, Lange L, Longstreth WT Jr, et al. Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study. J Thromb Haemost. 2011;9(2):267-74. doi:10.1111/j.1538-7836.2010.04149.x.

18. Ken-Dror G, Drenos F, Humphries SE, et al. Haplotype and genotype effects of the F7 gene on circulating factor VII, coagulation activation markers and incident coronary heart disease in UK men. J Thromb Haemost. 2010;8(11):2394-403. doi:10.1111/j.15387836.2010.04035.x.

19. Bairova TA, Gommellya MV, Dolgich VV, et al. Polymorphism (353)R>Q of gene of blood clotting factor VII and plasma hemostasis. Russ J Genet. 2016;52(2):214-9. doi:10.1134/S1022795415120030.

20. Mathilde H, Arnaldo A, Stanislaw L, et al. The Arg353Gln Polymorphism Reduces the Level of Coagulation Factor VII. In Vivo and in Vitro Studies. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2825-9. doi:10.1161/01.ATV.17.11.2825.

21. Zhang Y, Chen W, Chen LF, et al. Increased Urokinase-Type Plasminogen Activator Receptor Expression on Circulating Monocytes Is Correlated with Clinical Instability and Long-Term Adverse Cardiac Events in Patients with Coronary Artery Disease. Cardiology. 2016;135(2):98-107. doi:10.1159/000446392.

22. Liguori R, Quaranta S, Di Fiore R, et al. A novel polymorphism in the PAI-1 gene promoter enhances gene expression. A novel pro-thrombotic risk factor? Thromb Res. 2014;134(6):1229-33. doi:10.1016/j.thromres.2014.09.021.

23. Mani V, Woodward M, Samber D, et al. Predictors of change in carotid atherosclerotic plaque inflammation and burden as measured by 18-FDG-PET and MRI, respectively, in the dal-PLAQUE study. Int J Cardiovasc Imaging. 2014;30(3):571-82. doi:10.1007/s10554-014-0370-7.

24. DB SERPINE1 serpin family E member 1 [Homo sapiens (human)] — Gene — NCBI. (n.d.). Retrieved September 07, 2020. https://www.ncbi.nlm.nih.gov/gene/5054.

25. Ding J, Nicklas BJ, Fallin MD, et al. Plasminogen activator inhibitor type 1 gene polymorphisms and haplotypes are associated with plasma plasminogen activator inhibitor type 1 levels but not with myocardial infarction or stroke. Am Heart J. 2006;152(6):1109-15. doi:10.1016/j.ahj.2006.06.021.

26. Tsantes AE, Nikolopoulos GK, Bagos PG, et al. The effect of the plasminogen activator inhibitor-14G/5G polymorphism on the thrombotic risk. Thromb Res. 2008;122(6):736-42. doi:10.1016/j.thromres.2007.09.005.

27. Nikolopoulos GK, Bagos PG, Tsangaris I, et al. The association between plasminogen activator inhibitor type 1 (PAI-1) levels, PAI-14G/5G polymorphism, and myocardial infarction: a Mendelian randomization meta-analysis. Clin Chem Lab Med. 2014;52(7):937-50. doi:10.1515/cclm-2013-1124.

28. Liu Y, Cheng J, Guo X, et al. The roles of PAI-1 gene polymorphisms in atherosclerotic diseases: A systematic review and meta-analysis involving 149,908 subjects. Gene. 2018;673:167-73. doi:10.1016/j.gene.2018.06.040.