Combining family history of coronary heart disease and individual genetic predisposition to predict the risk of major coronary events: Selected Abstract - SITeCS Congress 2022

Background: Inherited predisposition to atherosclerosis leads to higher risk for developing coronary heart disease (CHD). There are mainly two ways to conceptualize inherited risk of CHD: family history and polygenic predisposition. We aimed at assessing the impact of family history of CHD and genetic predisposition in predicting the individual lifetime risk of major coronary events (MCE). Methods: Using adjusted Cox proportional hazard models, we estimated the lifetime risk of MCE associated with parental family history of CHD and individual genetic predisposition (estimated by a polygenic risk score including 350 variants). Results: A total of 445,744 UK-Biobank participants were included in the study (mean age 57 years; 54.3% females). Having one parent with a history of CHD increased the lifetime risk of MCE by 75% (HR 1.75, 95%CI 1.70-1.82). Having both parents with a history of CHD further increased the risk (HR 2.78, 95%CI 2.64-2.92) Similarly, a dose-dependent step-wise increase in MCE risk was observed moving from the lowest to the highest decile of the polygenic score. Compared to subjects without family history of CHD and with average level of the polygenic score, having a parental history of CHD determined an increase in lifetime risk of MCE (HR 1.90, 95%CI 1.82-1.98) comparable to belonging to the highest decile of the polygenic score (HR 1.89, 95%CI 1.76-2.02). However, if subjects present both parents with family history of CHD and a very high polygenic predisposition, the risk was even higher (HR 3.54, 95%CI 3.34-3.75), suggesting an additive contribution to the characterization of the lifetime risk. Conclusions: We described the addictive impact of family history of CHD and individual polygenic predisposition in predicting lifetime risk of MCE. In order to identify subjects at higher risk of having an early event, it is essential to retrieve information about both these hereditary components.