Interaction between type 2 diabetes polygenic risk and physical activity on cardiovascular outcomes

The beneficial effects of exercise on reducing the risk of cardiovascular disease are established. However, the potential interaction between genetic risk for type 2 diabetes and physical activity on cardiovascular outcomes remains elusive. We aimed to investigate the effect of type 2 diabetes genetic risk-physical activity interaction on cardiovascular outcomes in individuals with diabetes. Using the UK Biobank cohort, we investigated the effect of type 2 diabetes genetic risk-physical activity interaction on three-point and four-point major adverse cardiovascular events (MACE), in 25 701 diabetic participants. We used a polygenic risk score for type 2 diabetes (PRS_T2D) as a measure of genetic risk for type 2 diabetes. We observed a significant interaction between PRS_T2D and physical activity on cardiovascular outcomes (three-point MACE: P trend for interaction = 0.0081; four-point MACE: P trend for interaction = 0.0037). Among participants whose PRS_T2D was in the first or second quartile, but not in the third or fourth quartile, each 10 metabolic equivalents (METs) hours per week of physical activity decreased the risk of three-point or four-point MACE. Furthermore, restricted cubic spline analysis indicated that intense physical activity (>80 METs hours per week, which was self-reported by 12.7% of participants) increased the risk of cardiovascular outcomes among participants whose PRS_T2D was in the fourth quartile. Sub-group analysis suggested that negative impact of intense physical activity was observed only in non-insulin users. The beneficial effect of physical activity on cardiovascular outcomes disappeared among those with high genetic risk for type 2 diabetes.