Abstract Body (Do not enter title and authors here): Background: We investigated the impact of genetic risk factors for coronary heart disease (CHD) -polygenic risk score (PRS), 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).
Methods: CHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race/ethnicity (SIRE) was used as a population descriptor. We calculated a PRS for CHD (PRS_CHD, PGS004698), ascertained FH as the presence of pathogenic/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in first-degree relatives. We employed Pooled Cohort Equations (PCE) to estimate the 10y risk of CHD for adults ≥40y and modeled the association of conventional risk factors with CHD in adults <40y. AoU served as the training set, and eIV as the testing set. We analyzed the impact of PRS_CHD 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.
Results: We analyzed data for 19348 participants from eIV (age 50±15, 68% female, 41% non-White) and 239645 participants from AoU (age 55±17, 61% female, 48% non-White). Genetic risk factors were significantly associated with CHD. PRS_CHD performance varied by SIRE groups, while FamHx was consistent. The effects of PRS_CHD and FamHx on CHD were independent and additive (Figure 1). In adults ≥40y, incorporating PRS_CHD and FamHx into PCE improved discrimination (C-statistic increased from 0.719 to 0.753; P-diff=9.1×10^-3, Figure 2) and reclassified risk in 19% and 20% of participants at the 7.5% and 10% 10y CHD risk thresholds, respectively. Between the 7.5% and 10% 10y CHD risk thresholds, incorporating PRS_CHD and FamHx into the PCE improved the net benefit of the risk prediction models across White, Black, and Hispanic/Latino groups (Figure 3).
Conclusion: PRS_CHD and FamHx were independently and additively associated with CHD in two large diverse cohorts in the US. Incorporating PRS_CHD and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants, and improved net benefit of the PCE across all three major SIRE groups, motivating the addition of these factors to clinical risk calculators.