Impact of Genetic Risk Factors on Coronary Heart Disease Risk Across the Age Spectrum in Three Major Race/Ethnicity Groups in the United States

BackgroundMeasures of genetic predisposition can improve prediction of risk of cardiometabolic diseases but more data is needed in groups under-represented in genomics research. In this study, we investigated the impact of genetic risk factors for coronary heart disease (CHD) - polygenic risk, monogenic risk [in the form of familial hypercholesterolemia (FH)], and family history (FamHx) - on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults - eMERGE IV (eIV) and All of Us (AoU). MethodsCHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race/ethnicity (SIRE) was used as a population descriptor. We calculated a polygenic risk score for CHD (PRSCHD, PGS004698), ascertained FH as presence of pathogenic/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in a first-degree family member. We employed Pooled Cohort Equations (PCE) to estimate the 10-year risk of CHD for adults [&ge;]40 y and modeled the association of conventional risk factors with CHD in adults <40 y. We analyzed the impact of PRSCHD and FamHx on CHD risk estimates by a) using multivariable logistic regression and Cox proportional hazard models, assessing discrimination and the extent of risk reclassification; and b) net benefit analysis and decision curves to assess the performance of prediction models across actionable thresholds. ResultsWe analyzed data for 19,348 participants from eIV (age 50.6{+/-}15.0, 68% female, 40.5% non-White) and 239,645 participants from AoU (age 55.4{+/-}17.0, 60.6% female, 48% non-White). The effects of PRSCHD and FamHx on CHD were independent and additive in the two cohorts and incorporating both into PCE for eIV participants significantly improved discrimination (C-statistic increased from 0.719 to 0.753; P-diff=9.1x10-3) and reclassified risk in 18.7% and 20.2% of participants at the 7.5% and 10% 10-y CHD risk thresholds, respectively. Between the 7.5% and 10% 10-y CHD risk thresholds, incorporating PRSCHD and FamHx into the PCE improved the net benefit of the risk prediction models across all SIRE groups. ConclusionPRSCHD and FamHx were independently and additively associated with CHD across major SIRE groups in two diverse cohorts in the US. Incorporating PRSCHD and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants at actionable 10-y CHD risk thresholds, and improved net benefit of the PCE, motivating the addition of these factors to clinical risk algorithms.