Genetic determinants of coronary resilience: why do some high-risk individuals escape coronary artery disease?

Introduction Coronary artery disease (CAD) remains the leading cause of cardiovascular morbidity and mortality. Traditional cardiovascular risk factors are well established; however, some high-risk individuals remain event-free, whereas others develop CAD, suggesting that genetic variability may influence individual susceptibility. Objectives Assess whether selected genetic polymorphisms differ between high-risk individuals who developed CAD and high-risk controls who remain event-free, and determine whether specific alleles confer protection or increased vulnerability to CAD. Methods A retrospective case–control study was conducted including 1,067 with confirmed CAD (>70% stenosis in one major coronary artery; 73.8% men, aged 58.41±7.9 years) and 435 high-risk controls (73.9% men, aged 58.41±3.9 years) (≥3 classical CVRFs: hypertension, diabetes, dyslipidaemia, obesity, active smoking, eGFR <60 mL/min/1.73m² or positive family history). Thirty-three genetic polymorphisms previously associated with CAD were genotyped using TaqMan real-time PCR. Logistic regression was used to identify independent predictors of CAD, adjusting for age and sex. Bivariate analysis evaluated differences in genetic variants. Results Among high-risk participants, the LPA rs3798220 TC genotype was significantly more frequent in CAD patients (p=0.004), conferring a 2.5-fold higher likelihood of CAD (OR 2.50, 95% CI 1.31–4.79; p=0.006). The TT genotype predominated in resilient controls, suggesting a protective effect. For PON55 rs854560 LM, the MM genotype was more common among CAD cases and remained independently associated with CAD after adjustment (OR 1.73, 95% CI 1.21–2.48; p=0.003). The LL genotype was more prevalent in controls, again suggesting possible protection. Overall, individuals who remained event-free despite similar clinical risk profiles showed a lower prevalence of risk-associated genotypes (LPA TC and PON55 MM), supporting a genetic contribution to disease resilience. Conclusion In a population uniformly exposed to high clinical risk, genetic background significantly differentiated individuals who developed CAD from those who remained event-free. PON55 M risk allele has higher enzymatic activity, promoting atherosclerosis, while the LPA C risk allele influences Lp(a) levels, contributing to thrombus formation. These findings support the concept that genetic background moderates the biological CAD vulnerability and may partially explain why some "ticking time bombs" remain free of disease.Genetic determinants of Coronary Resilience