Polygenic susceptibility modifies the association between long-term physical activity patterns and major adverse cardiovascular events: Insights from a target trial emulation study

Physical activity is a key modifiable lifestyle factor for cardiovascular prevention. However, precise prevention strategies regarding long-term physical activity are lacking, particularly concerning whether genetic susceptibility modifies the association between long-term physical activity and major adverse cardiovascular events (MACE). Most previous cohort studies rely on a single assessment of physical activity, which may not capture long-term behavior. To address these gaps, we used repeated assessments and a target trial emulation framework in UK Biobank.

We studied 27,459 UK Biobank participants with repeat physical activity assessments. A target trial emulation framework defined eligibility, time zero, exposure groups, and follow-up. The prespecified primary contrast compared increased physical activity with sustained low activity after 1:1 propensity score matching. Secondary full-cohort models examined four physical activity change patterns. Cardiovascular polygenic risk strata were evaluated exploratorily.

In 4401 matched pairs, increased physical activity was not significantly associated with lower major adverse cardiovascular events (MACE) compared with sustained low activity (HR 1.19, 95% CI 0.90-1.58). In full-cohort models, sustained high physical activity was associated with higher MACE risk (HR 1.27, 95% CI 1.03-1.56). This signal was more apparent among participants with intermediate or high cardiovascular polygenic risk.

In this UK Biobank target trial emulation, increasing physical activity from low levels did not clearly reduce MACE, whereas sustained high activity showed an unexpected higher-risk signal, particularly among genetically susceptible participants. These findings support the potential value of genetic risk assessment in cardiovascular risk evaluation for highly active individuals and provide new evidence for precision exercise prescriptions.