<i>PCSK9</i> gene Polymorphism and Assessment of Cardiovascular Risk and Prognosis in Patients With Hyperlipidemia: A Retrospective Cohort Study

Proprotein convertase subtilisin/kexin type 9 (PCSK9) polymorphisms exhibit ethnic-specific associations with cardiovascular risk. However, their prognostic value for major adverse cardiovascular and cerebrovascular events (MACCE) in Asian populations remains undefined. This prospective cohort study enrolled 1969 patients (mean age 54.5 ± 10.7 years, 60.2% male) with hyperlipidemia and followed them for a median of 62 months (IQR 24-89 months). We evaluated the association of three PCSK9 polymorphisms (rs2483205, rs2495477, and rs562556) with metabolic parameters and MACCE. A genotype-integrated nomogram was developed using Least Absolute Shrinkage and Selection Operator (LASSO) - selected predictors and validated in an independent cohort. The rs2483205 TT, rs2495477 GG, and rs562556 GG genotypes were significantly associated with atherogenic dyslipidemia (elevated triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a) [Lp(a)], all p < 0.001) and predicted MACCE risk independently of conventional factors (HR = 2.94, 95% CI: 1.80-4.80 for rs2483205 TT). The nomogram demonstrated excellent discrimination (3 and 4 year area under the curve (AUC) = 0.989, concordance index (C-index) = 0.868) and calibration (slope = 1.02, 95% CI: 0.98-1.06), with decision curve analysis confirming clinical utility across risk thresholds (20%-75%). Net Reclassification Improvement (NRI) increase of 0.059 and an Integrated Discrimination Improvement (IDI) increase of 0.022. PCSK9 genotyping provides independent prognostic value for MACCE risk stratification in hyperlipidemia, with genotype-specific effects on cardiovascular outcomes. The developed nomogram offers a precision medicine tool for individualized risk prediction and therapeutic decision-making.