Contribution and interaction of polygenic predisposition and family history of coronary heart disease in predicting cardiovascular risk.

Background And Aim: Inherited susceptibility to coronary heart disease (CHD) can be conceptualized by considering family history and polygenic predisposition. This study aimed to clarify the role of these two components in predicting individual lifetime risk.

Methods: In the UK Biobank, information about family history of CHD (having one or both parents with CHD) was recorded at enrolment. To assess each individual's polygenic predisposition, we employed a previously validated polygenic risk score (PRS). Adjusted Cox models were used to analyse the impact of family history and PRS on major coronary events (MCE).

Results: We included a total of 404,654 participants (mean age 57 years; 55.3 % females). Both family history and PRS were found to be dose-related with the lifetime risk of MCE. Having a parental history of CHD or having a very high PRS (10th decile) exhibited a similar increasing effect, in terms of lifetime risk of MCE (12 % with hazard ratio [HR]: 1.86, 95 % confidence intervals [CI]: 1.80-1.94, and 14 % with HR: 1.93, 95 %CI: 1.81-2.05, respectively). The presence of a very high PRS, on top of a positive parental history of CHD, further increased the risk (20 % with HR: 3.54, 95 %CI: 3.37-3.73). Even after stratifying by LDL-C levels, both family history and polygenic predisposition complementary and additively contributed to MCE risk increase.

Conclusions: Family history and polygenic predisposition are both impactful predictors of MCE risk, demonstrating an additive effect that underscores the importance of considering these factors alongside cardiovascular risk factors for a comprehensive assessment of individual cardiovascular risk.