Background: We aimed to investigate the associations between polygenic risk score (PRS) for T2DM and future risk of cardiovascular disease (CVD) in middle-aged UK Biobank participants of European ancestry.

Methods: We used data from UK Biobank participants aged 40-69 years at baseline, registered from 22 assessment centers across the United Kingdom with standardized procedures. Genome-wide PRSs were constructed using >9 million genetic variants, and newly developed myocardial infarction (MI), ischemic stroke, and cardiovascular (CV) mortality were considered as outcomes. Cox proportional hazard models were used to analyze the relationship between PRSs and CV mortality with stratification by age, sex, and lifestyle behavior.

Results: Of 362,405 participants having European ancestry, 8,787 (2.4%) experienced cardiovascular events and 2,414 (0.7%) died due to CVD during a median follow-up of 8.9 years. Risk of CV mortality and of myocardial infarction (MI) were both significantly associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.73 [1.23-2.44] and HR of MI 1.55 [1.24-1.96], P <0.001). By contrast, the risk of ischemic stroke was not associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.24 [0.87-1.79], P =0.232). Adherence to an unfavorable lifestyle in the very high genetic risk group was further associated with a substantially increased risk of CV mortality (HR 6.38 [3.46-11.77]) and with risk of MI (HR 3.28 [2.02-5.32]). There was no evidence of significant interaction between PRS and lifestyle behavior in predicting the risk of CVD.

Conclusion: PRS for T2DM is an independent predictive factor for future CVD and associated mortality in the white, middle-aged population. PRS-based genetic risk assessment could be useful to identify individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CVD.


S. Jung: None. D. Kim: None. M. Shivakumar: None. H. Won: None. J. Yun: None.

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