Association of PCSK6 rs1531817(C/A) polymorphism with the prognosis and coronary stenosis in premature myocardial infarction patients: a prospective cohort study

Abstract Background An increasing proportion of younger patients are currently hospitalized for acute myocardial infarction. Exploring the factors affecting coronary artery lesions and prognosis in patients with premature myocardial infarction (PMI) from a genetic perspective is of great significance to clinical management. Proprotein convertase subtilisins/kexins 6(PCSK6), a member of the PCSK family, functions in protein hydrolytic cleavage. It has been shown that PCSK6 polymorphisms are associated with carotid atherosclerosis. Purpose This research intended to evaluate the relationship between the PCSK6 rs1531817 polymorphism and the prognosis of PMI patients and their coronary stenosis. Methods This study was a prospective cohort study, which consecutively included 605 patients with PMI who underwent emergency PCI from January 2017 to August 2022 at X Hospital. Using the Massarray technique, the single nucleotide polymorphisms(SNPs) of PCSK6 rs1531817 were identified, and the patients underwent follow-up for 12 to 72 months, with major adverse cardiovascular events (MACEs) as the outcome. Analyze the relationship between patients' SNPs, Gensini score(GS), Triple vessel diseases(TVD), and MACEs. Results In PMI patients with PCSK6 rs1531817 CA+AA genotypes, ApoA1/ApoB levels were higher than in patients with CC genotype, and TC/HDL levels were lower (p < 0.05). Logistic regression analysis showed that the PCSK6 rs1531817 polymorphism (Dominant model: CA+AA vs.CC) was significantly correlated with the GS (high vs. low GS, adjOR=0.297, 95%CI:0.139-0.632, p=0.002; high vs. medium GS, adjOR=0.449, 95%CI:0.211-0.956, p=0.038), and it was correlated with the number of coronary artery lesions (TVD vs. SVD, adjOR=0.420, 95%CI:0.226-0.782, p=0.006; TVD vs. DVD, adjOR=0.406, 95%CI:0.214-0.773, p=0.006). According to multivariate Cox regression analysis, the PCSK6 rs1531817 dominant model was associated with the MACEs in PMI patients (adjHR=0.454, 95%CI:0.269-0.766, p=0.003). The mediation effect results showed that ApoA1/ApoB played a partially mediating role in the association between PCSK6 rs1531817 polymorphism and the severity of coronary stenosis (the effect leading to high GS and TVD accounted for 14.6% and 8.3% respectively), TC/HDL and TVD partially parallel mediated the association between PCSK6 rs1531817 polymorphism and MACEs (effect proportions were 8.1% and 17.1%, respectively). Conclusion Carrying the PCSK6 rs1531817 mutant A allele is an independent protective predictor of severe coronary stenosis and long-term prognosis in patients with PMI. Patients with the PCSK6 CA+AA genotypes have milder coronary stenosis partially because they have higher levels of ApoA1/ApoB; in addition, these patients have a better long-term prognosis partially because they have lower TC/HDL levels and fewer TVD patients.Figure 1.ApoA1/ApoB and TC/HDL were compareFigure 2.Correlation of PCSK6 rs1531817 pol