Dynamic lifestyle trajectories, polygenic risk, and incident coronary artery disease: a longitudinal study in the UK biobank

Background Cardiovascular disease is a leading cause of global morbidity and mortality, driven by both genetic and lifestyle factors. While genetic predisposition to coronary artery disease (CAD) is well-established, whether dynamic lifestyle changes can modify this inherited risk remains unclear. Purpose To investigate the interaction between polygenic risk for CAD and longitudinal lifestyle trajectories, and determine whether favorable lifestyle changes are associated with reduced CAD risk, particularly among those with high genetic susceptibility. Methods This prospective cohort study used data from the UK Biobank, which includes over 500,000 participants aged 40–69 years, recruited between 2006 and 2010. The analysis focused on participants of European ancestry with available genotype, polygenic risk scores (PRS) for CAD, and lifestyle data from at least two time points. A composite lifestyle score was created based on smoking, sleep, physical activity, diet, and body mass index. Lifestyle trajectories were modeled using group-based trajectory modeling, dividing participants into different lifestyle patterns. Incident CAD was defined as the first CAD-related event during follow-up, identified through hospital records, procedural codes, and death registries. Genetic risk for CAD was assessed using the UK Biobank enhanced PRS, categorized into low, intermediate, and high-risk groups. Cox proportional hazards models were used to analyze the links between lifestyle patterns, genetic risk, and CAD incidence. Results A total of 315,000 participants were followed for an average of 12.5 years, identifying four distinct lifestyle trajectories. Compared to the stable healthy group, those with a stable unhealthy lifestyle had a significantly higher risk of CAD (hazard ratio [HR] 1.82, p<0.001). The improving lifestyle group had a moderate increase in risk (HR 1.22, p<0.001), but lower than the stable unhealthy group. A significant interaction was found between lifestyle trajectory and genetic risk (p<0.001). For those with high genetic risk, a stable unhealthy lifestyle nearly tripled the risk of CAD compared to those with a stable healthy lifestyle (HR 2.95, p<0.001). However, high-risk individuals who improved their lifestyle saw a 44% risk reduction (HR 1.65, p<0.001). Among low genetic risk individuals, the effect of an unhealthy lifestyle was less severe (HR 1.35, p<0.001). Kaplan-Meier curves showed the highest CAD incidence in the high genetic risk-unhealthy lifestyle group. Conclusion Genetic susceptibility and lifestyle trajectories jointly determine the risk of incident CAD. Improving lifestyle behaviors, even in adulthood, may substantially attenuate the excess risk conferred by high polygenic risk.