Association between genetic polymorphisms in multiple thrombosis-related genes and long-term prognosis in coronary artery disease patients: a large-scale cohort study

Abstract Background Coronary artery disease (CAD) is a leading cause of mortality worldwide, with thrombosis playing a critical role in its pathogenesis. Coagulation factors and other molecules involved in thrombosis and fibrinolysis have become important biomarkers and therapeutic targets. Recently, genetic risk assessment has garnered increasing attention. Despite these advances, the role of thrombosis-related genetic polymorphisms in the prognosis of CAD patients remains poorly understood. Purpose The objective of this study was to explore the relationship between single nucleotide polymorphisms (SNP) in multiple thrombosis-related genes and the long-term prognosis of CAD patients. Additionally, we intended to investigate the interactions between these genetic variants and other clinical factors. Methods This study enrolled a large-scale prospective cohort of 4,304 consecutive patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) and provided valid blood samples for DNA analysis. We genotyped and analyzed nine single SNPs in the THBD, F2, F5, and F12 genes. Patients were followed up for 5 years, with the primary endpoint defined as major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause death, non-fatal myocardial infarction, stroke, and coronary revascularization. Results The average age of the study population was 57.45±10.14 years, with 571 (75.1%) patients being male. During a median follow-up of 5.06 years, 934 (21.7%) patients experienced MACCE. Multivariable Cox regression analysis revealed that the rs2269648 (CT) polymorphism in F5 was significantly associated with an increased risk of MACCE in the recessive model. In contrast, the rs7542281 (CT) polymorphism in F5 was significantly associated with a decreased risk of MACCE in the overdominant model. Moreover, the homozygous rs1801020 (AG) polymorphism in F12 was associated with a significantly lower risk of MACCE. Further analysis revealed significant interactions between two SNPs in the F5 gene, rs2269648 and rs7542281, and dyslipidemia (P for interaction 0.05). The heterozygous rs2269648 mutation carriers with dyslipidemia had a 1.489-fold increased risk of MACCE (HR: 1.489；95% CI: 1.210-1.833, P 0.001), while the homozygous rs7542281 mutation carriers without dyslipidemia had a 0.576-fold reduced risk (HR: 0.576；95% CI: 0.449-0.740, P 0.001). Conclusion This study highlights the role of thrombosis-related genetic polymorphisms in predicting long-term outcomes in CAD patients. Genetic variants in F5 (rs2269648 and rs7542281) and F12 (rs1801020) were identified to be strongly associated with prognosis, particularly when considering interactions with dyslipidemia. Future studies are needed to explore the underlying mechanisms and further validate these findings.Association of SNPs with 5-year MACCE Interaction between factors