Association of the T1565C (rs5918) polymorphism of the ITGB3 gene with clinical characteristics, anatomical features and long-term adverse events in patients with chronic coronary artery disease after elective endovascular coronary interventions

Background. The T1565C (dbSNP ID: rs5918) polymorphism of the integrin gene (ITGB3) is a risk factor for many diseases such as coronary heart disease (CHD), venous thrombosis, and oncology.

The minor allele C is known to alter aspirin sensitivity and increase platelet aggregation, which may affect the incidence of cardiovascular complications after elective percutaneous coronary interventions (PCI).

Aim: To study the association of the T1565C (rs5918) polymorphism of the ITGB3 gene with clinical characteristics, anatomical features and long-term adverse events after elective PCI in patients with chronic CHD.

Material and methods. The study included 364 patients with chronic CHD from a registry of elective PCI performed at the Research Institute of Cardiology of the Tomsk National Research Medical Center from 2010 to 2017. The association of polymorphic variants of rs5918 of the ITGB3 gene with long-term (5-year) adverse events was assessed using genotype frequency analysis and odds ratio (OR). Adverse events included death from cardiovascular and other causes, myocardial infarction (MI), stroke (CVA), and concomitant oncological diseases.

Results. The genotype frequencies were: TT – 69.2%, TC – 28%, CC – 2.8%. The frequencies of T and C alleles were 83.2% and 16.8%. The presence of the T allele was associated with concomitant carbohydrate metabolism disorders in patients (OR = 1.502; CI [1.005–2.247]; S = 0.205; p = 0.047). The Charlson comorbidity index was higher in the group of carriers of the minor homozygous CC genotype compared to carriers of the T allele (TC + TT groups) (Me (Q1–Q3); 4(3–5) vs 3(2–4), respectively, p = 0.025). No association was found between the rs5918 polymorphism of the ITGB3 gene and late adverse cardiovascular events and death from all causes. In the presence of the minor homozygous CC genotype, the chances of concomitant oncological diseases significantly increase (OR = 5.750; CI [1.359–24.335], S = 0.736, p = 0.035).

Conclusion. The rs5918 polymorphism of the ITGB3 gene is associated with phenotype-specific characteristics of patients with chronic coronary artery disease who are eligible for elective PCI. These characteristics include varying degrees of comorbidity (as measured by the Charlson index), the frequency of carbohydrate metabolism disorders and cancer, as well as the severity and location of coronary lesions, which may impact the completeness of revascularization and the long-term prognosis of these patients.

1. Maron D.J., Hochman J.S., Reynolds H.R. et al.; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N. Engl. J. Med. 2020;382(15):1395–1407. https://doi.org/10.1056/NEJMoa1915922

2. Vershininа E.O., Repin A.N., Ryabova T.R. The impact of multifocal atherosclerosis on the early and late outcomes of elective endovascular treatment of ischemic heart disease. Siberian Journal of Clinical and Experimental Medicine. 2014;29(3):87–93. (In Russ.) https://doi.org/10.29001/2073-8552-2014-29-3-87-93

3. Nguyen M.T., Ali A., Ngo L. et al. Thirty-day unplanned readmissions following elective and acute percutaneous coronary intervention. Heart Lung Circ. 2023;32(5):619–628. https://doi.org/10.1016/j.hlc.2023.02.013

4. Nalesnik E.O., Repin A.N. Risk assessment of remotely fatal cardiovascular events after elective percutaneous coronary intervention. Complex Issues of Cardiovascular Diseases. 2022;11(3):40–50. (In Russ.) https://doi.org/10.17802/2306-1278-2022-11-3-40-50

5. Yager N., Schulman-Marcus J., Torosoff M. Coronary anatomy and comorbidities impact on elective PCI outcomes in left main and multivessel coronary artery disease. Catheter Cardiovasc. Interv. 2021;98(3):436–444. https://doi.org/10.1002/ccd.29368

6. Zhao Y., Tu X. Editorial for the Molecular Genetics and Genomics of Metabolic Disorders in Cardiovascular and Cerebrovascular Diseases Special Issue: June 2023. Genes (Basel). 2023;14(8):1568. https://doi.org/10.3390/genes14081568

7. Bachmann M., Kukkurainen S., Hytönen V.P., Wehrle-Haller B. Cell Adhesion by Integrins. Physiological Reviews. 2019;99(4):1655–1699. https://doi.org/10.1152/physrev.00036.2018

8. Khatami M., Heidari M.M., Soheilyfar S. Common rs5918 (PlA1/A2) polymorphism in the ITGB3 gene and risk of coronary artery disease. Archives of Medical Science – Atherosclerotic Diseases. 2016;1(1):e9– e15. https://doi.org/10.5114/amsad.2016.59587

9. Todinova S., Komsa-Penkova R., Krumova S. et al. PlA2 Polymorphism in Glycoprotein IIb/IIIa Modulates the Morphology and Nanomechanics of Platelets. Clin. Appl. Thromb. Hemost. 2017;23(8):951–960. https://doi.org/10.1177/1076029616687847

10. Sheikhvatan M., Boroumand M.A., Behmanesh M. Integrin Beta-3 gene polymorphism and risk for myocardial infarction in premature coronary disease. Iran J. Biotechnol. 2019;17(2):e1921. https://doi.org/10.21859/ijb.1921

11. Tschoepe D., Menart B., Ferber P. et al. Genetic variation of the platelet-surface integrin GPIIb-IIIa (PIA1/A2-SNP) shows a high association with Type 2 diabetes mellitus. Diabetologia. 2003;46(7):984–989. https://doi.org/10.1007/s00125-003-1132-6

12. Wang G., Wang D., Sun M. et al. Identification of prognostic and immune-related gene signatures in the tumor microenvironment of endometrial cancer. Int. Immunopharmacol. 2020;88:106931. https://doi.org/10.1016/j.intimp.2020.106931

13. Cooke G.E., Liu-Stratton Y., Ferketich A.K. et al. Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination. J. Am. Coll. Cardiol. 2006;47(3):541–546. https://doi.org/10.1016/j.jacc.2005.09.034

14. Barbarash O. L., Karpov Yu. A., Kashtalap V.V. et al. 2020 Clinical practice guidelines for stable coronary artery disease. Russian Journal of Cardiology. 2020;25:4076. (In Russ.). https://doi.org/10.15829/1560-4071-2020-4076

15. Neumann F.J., Sousa-Uva M., Ahlsson A. et al.; ESC Scientific Document Group. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur. Heart J. 2019;40(2):87–165. https://doi.org/10.1093/eurheartj/ehy394

16. Nalesnik E.O., Svarovskaya A.V., Repin A.N., Trubacheva I.A. A 5-year follow-up database of patients with chronic coronary syndrome who underwent elective percutaneous coronary interventions. Certificate of registration No. 2024621119. Date of registration: March 14, 2024. (RU).

17. Goncharova I.A., Babushkina N.P., Minaycheva L.I. et al. Prevalence of Alleles of Polymorphic Variants Leu33Pro and Leu66Arg Gene ITGB3 among Inhabitants of Siberia. Genetics. 2013;49(8):1008–12. (In Russ.). https://doi.org/10.7868/S0016675813070059

18. Patrono C., Rocca B. Type 2 Diabetes, Obesity, and Aspirin Responsiveness. J. Am. Coll. Cardiol. 2017;69(6):613–615. https://doi.org/10.1016/j.jacc.2016.11.049

19. Janus-Bell E., Mangin P.H. The relative importance of platelet integrins in hemostasis, thrombosis and beyond. Haematologica. 2023;108(7):1734–1747. https://doi.org/10.3324/haematol.2022.282136

20. Liu F., Wu Q., Dong Z., Liu K. Integrins in cancer: Emerging mechanisms and therapeutic opportunities. Pharmacol. Ther. 2023;247:108458. https://doi.org/10.1016/j.pharmthera.2023.108458

21. Stremitzer S., Berghoff A.S., Volz N.B. et al. Genetic variants associated with colorectal brain metastases susceptibility and survival. Pharmacogenomics J. 2017;17(1):29–35. https://doi.org/10.1038/tpj.2015.86