Polygenic risk for type 2 diabetes, multiple risk factor control, and cardiovascular and non-cardiovascular mortality: a prospective UK biobank study
Z Zhang, Z Zhang, J wang, X zhou, X meng, Y liuAbstract
Aim
This study explored associations between type 2 diabetes mellitus (T2DM) genetic susceptibility, multiple cardiovascular risk factor control, and cardiovascular/non-cardiovascular mortality in the general population, as well as their interactions, to inform precise cardiovascular mortality prevention in T2DM genetically high-risk groups.
Methods
Using prospective data from 319,506 UK Biobank participants, a T2DM polygenic risk score (PRS) categorized individuals into low, intermediate, and high genetic risk groups. Seven modifiable cardiovascular risk factors were assessed, with participants divided into unfavorable (0-2 factors controlled), moderate (3-4 factors), and favorable (5-7 factors) control groups. Cox proportional hazards regression analyzed associations with all-cause, cardiovascular disease (CVD), cancer, and other-cause mortality. Interactions were evaluated via interaction terms, with robustness verified by subgroup and sensitivity analyses.
Results
Over a median 11.2-year follow-up, 24,545 all-cause, 4,966 CVD, 12,397 cancer, and 7,182 other-cause deaths occurred. After multivariate adjustment, the high genetic risk group had 13% higher all-cause (HR=1.13, 95% CI:1.09-1.18, P<0.001) and 36% higher CVD (HR=1.36, 95% CI:1.25-1.49, P<0.001) mortality vs. the low-risk group, with no significant association with cancer mortality (HR=1.04, 95% CI:0.98-1.10, P=0.189). The favorable control group had 21% lower all-cause (HR=0.79, 95% CI:0.76-0.82), 35% lower CVD (HR=0.65, 95% CI:0.59-0.71), and 25% lower cancer (HR=0.75, 95% CI:0.71-0.80) mortality vs. the unfavorable group (all P<0.001). Significant interactions between T2DM genetic risk and risk factor control were observed for all-cause and CVD mortality (P<0.001): the high genetic risk + unfavorable control combination had the highest risk (all-cause HR=1.65; CVD HR=2.34, both P<0.001). Even with favorable control, high genetic risk individuals had increased all-cause (HR=1.15, P<0.001) and CVD (HR=1.23, P=0.017) mortality. Subgroup and sensitivity analyses confirmed robustness.
Conclusions
T2DM genetic susceptibility is an independent risk factor for all-cause and CVD mortality. Favorable multiple cardiovascular risk factor control reduces various mortality risks, with significant interactions between T2DM genetic risk and risk factor control for all-cause and CVD mortality. T2DM genetically high-risk individuals are key targets for cardiovascular mortality prevention; early, intensive comprehensive risk factor management maximizes mortality reduction, providing evidence for precise prevention.tablefigure