Key result
Very high CAD polygenic risk linked to ~160% higher CV mortality vs. low risk.
Why the study?
Previous studies mainly focused on PRSs predicting specific diseases, with limited investigation of their association with cardiovascular mortality and interaction with lifestyle.
Do polygenic risk scores for CAD and T2DM, along with lifestyle behaviors, predict cardiovascular mortality in middle-aged individuals of European ancestry?
Cohort (n=377,909)
Yes
Do polygenic risk scores for CAD and T2DM, along with lifestyle behaviors, predict cardiovascular mortality in middle-aged individuals of European ancestry?
Hazard Ratio: 2.61 (95% CI 2.02–3.36)
p-value: p=<0.001
Polygenic risk scores for CAD and T2DM, along with lifestyle behaviors, are independent predictive factors for future cardiovascular mortality, highlighting the potential for PRS-based risk assessment to guide intensive interventions.
PRS for CAD and T2DM independently associated with CV mortality; extends genetic prediction data but remains hypothesis-generating and should not change practice.
Background: Previous studies primarily targeted the ability of polygenic risk scores (PRSs) to predict a specific disease, and only a few studies have investigated the association between genetic risk scores and cardiovascular (CV) mortality. We assessed PRSs for coronary artery disease (CAD) and type 2 diabetes (T2DM) as the predictive factors for CV mortality, independent of traditional risk factors, and further investigated the additive effect between lifestyle behavior and PRS on CV mortality. Methods: We used genetic and phenotypic data from UK Biobank participants aged 40-69 years at baseline, collected with standardized procedures. Genome-wide PRSs were constructed using >6 million genetic variants. Cox proportional hazard models were used to analyze the relationship between PRS and CV mortality with stratification by age, sex, disease status, and lifestyle behavior. Results: Of 377,909 UK Biobank participants having European ancestry, 3,210 (0.8%) died due to CV disease during a median follow-up of 8.9 years. CV mortality risk was significantly associated with CAD PRS [low vs. very high genetic risk groups, CAD PRS hazard ratio (HR) 2.61 (2.02-3.36)] and T2DM PRS [HR 2.08 (1.58-2.73)], respectively. These relationships remained significant even after an adjustment for a comprehensive range of demographic and clinical factors. In the very high genetic risk group, adherence to an unfavorable lifestyle was further associated with a substantially increased risk of CV mortality [favorable vs. unfavorable lifestyle with very high genetic risk for CAD PRS, HR 8.31 (5.12-13.49); T2DM PRS, HR 5.84 (3.39-10.04)]. Across all genetic risk groups, 32.1% of CV mortality was attributable to lifestyle behavior [population attributable fraction (PAF) 32.1% (95% CI 28.8-35.3%)] and 14.1% was attributable to smoking [PAF 14.1% (95% CI 12.4-15.7%)]. There was no evidence of significant interaction between PRSs and age, sex, or lifestyle behavior in predicting the risk of CV mortality. Conclusion: PRSs for CAD or T2DM and lifestyle behaviors are the independent predictive factors for future CV mortality in the white, middle-aged population. PRS-based risk assessment could be useful to identify the individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CV mortality.
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Yun et al. (2022) conducted a cohort in Cardiovascular mortality risk (n=377,909). Very high polygenic risk score for coronary artery disease vs. Low polygenic risk score was evaluated on Cardiovascular mortality (HR 2.61, 95% CI 2.02-3.36, p=<0.001). Very high polygenic risk for coronary artery disease was independently associated with a 2.6-fold increased risk of cardiovascular mortality (HR 2.61) compared to low genetic risk.
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