Physical activity, genetic predisposition, and incident cardiovascular disease: Prospective analyses of the UK Biobank

It is unclear whether physical activity can benefit participants with high genetic predisposition to cardiovascular disease. We examined the joint associations of intensity-specific physical activity and genetic predisposition (based on polygenetic risk score) with incident coronary heart disease (CHD), stroke, and atrial fibrillation (AF). This prospective cohort study included 303,950 adults (age = 56.4 ± 8.0 years, mean ± SD; 52.5% females) from the UK Biobank with physical activity and disease-related genotypes. Moderate-to-vigorous physical activity (MVPA) and intensity-specific activity was classified according to volume (e.g., MVPA was classified as none, low, medium, and high). Genetic predisposition for CHD, stroke, and AF were classified as low (Quintile 1), intermediate (Quintiles 2-4), and high (Quintile 5). During 11.6 ± 2.1 years of follow-up: 19,865 CHD; 7907 stroke; and 16,688 AF events occurred. Compared to the no MVPA and high genetic risk group, we observed lower CHD risk for increasing levels of MVPA over and above genetic risk groupings. These associations were primarily driven by vigorous-intensity activity. For example, in the high genetic risk group, those with low vigorous-intensity activity levels (compared to none) had a hazard ratio (HR) of 0.78 (95% confidence interval (95%CI):0.72-0.86) compared to an HR of 0.90 (95%CI: 0.83-0.98) for low moderate-intensity activity levels. For stroke incidence, we observed a protective association for MVPA across genetic risk groups that was mostly driven by moderate-intensity activity volume. Among the high genetic risk group, low moderate-intensity had an HR of 0.77 (95%CI:0.66-0.90), whereas low vigorous-intensity had no association (HR = 0.95, 95%CI:0.82-1.09). We did not observe a consistent joint association of MVPA and AF genetic predisposition. We observed lower CHD and stroke risk for low to high MVPA among participants with high genetic predisposition. The associations of moderate- and vigorous-intensity activity volume differed considerably across cardiovascular disease sub-types. Overall, our findings suggest vigorous intensity activity may mitigate genetic predisposition for CHD while moderate intensity activity may be associated with similar effects for stroke. Joint associations were less consistent across AF genetic predisposition groups. Our results inform precision medicine approaches and future lifestyle modification interventions by quantifying the potential benefits of physical activity among at-risk individuals.