Association of genetic risk and physical activity with incident type 2 diabetes

OBJECTIVE: To assess whether daily step counts and genetic risk interact to influence the risk of developing type 2 diabetes.

RESEARCH DESIGN AND METHODS: We analyzed data from 9,501 participants in the All of Us Research Program with both genetic and wearable device-derived physical activity data and without diabetes at baseline and median age of 56 years (42-66). Physical activity was quantified using daily step counts. Genetic risk was assessed using a global polygenic score. Incident type 2 diabetes was identified using electronic health record-linked diagnostic codes. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) for type 2 diabetes across genetic risk and physical activity levels. We tested for additive interaction using the relative excess risk due to interaction (RERI). In secondary analyses we used physical-activity intensity measures using wearable-derived and self-reported intensity levels.

RESULTS: Type 2 diabetes incidence rates ranged from 4.1 per 1,000 person-years (95% CI, 2.5-5.7) in individuals with high physical activity and low genetic risk to 18.4 (95% CI, 15.2-21.6) in those with low physical activity and high genetic risk (HR, 6.2 (95% CI: 3.97, 9.6)). A significant additive interaction was observed (RERI, 0.20; 95% CI, 0.04-0.36; P = .007), with 15% (95% CI, 2-27) of excess risk attributed to the interaction. Similar interaction patterns were found using device-based intensity metrics and self-reported physical activity measures.

CONCLUSIONS: These findings provide evidence of additive interactions between genetic risk and physical activity, underscoring the potential value of integrating genomic and device-derived data to identify individuals who would more likely benefit from increasing physical activity.