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

Figures

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  Figure 1:. Study Design Three genetic risk factors—PRSCHD, FH, and FamHx—were ascertained in two diverse cohorts in the U.S.: eIV and AoU. We assessed the association of genetic risk factors with all CHD cases (prevalent CHD) in eIV, and incident CHD in AoU. We utilized AoU data to derive coefficients for PCE, PRSCHD, and FamHx when incorporated into a risk prediction model, PCE, for individuals aged 40 and older in eIV. Abbreviations: CHD: coronary heart disease, FamHx: family history, PRSCHD: polygenic risk score for CHD, PCE: pooled cohort equations, srWGS: short-read whole genome sequencing

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  Figure 2:. Additive Effect of PRSCHD and FamHx on CHD in eIV and AoU Abbreviations: AoU: All of Us research program, CHD: coronary heart disease, CI: confidence interval, eIV: eMERGE IV study, FamHx: family history, PRS: polygenic risk score for CHD

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  Figure 3:. C-statistic of Logistic Regression Models for Presence of CHD in Younger and Older Adults in eIV The left panel presents the C-statistic (95% CI) for different prediction models in adults younger than 40 years. Model 1 included demographic data and ASCVD risk factors (systolic blood pressure, total cholesterol, current smoking status, and lipid-lowering therapy). Model 2 further included PRSCHD, and Model 3 added both PRSCHD and FamHx to Model 1. The right panel shows the C-statistic (95% CI) for prediction models in adults older than 40 years. The inclusion of PRSCHD (Model 2) and the combination of PRSCHD and FamHx (Model 3) led to improved CHD risk discrimination. Abbreviations: ASCVD: atherosclerotic cardiovascular disease, CHD: coronary heart disease, CI: confidence interval, eIV: eMERGE IV study, FamHx: family history of CHD, PCE: pooled cohort equations, PRSCHD: polygenic risk score for CHD

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  Figure 4:. Decision Curve Analysis of CHD Prediction Models Across Actionable Risk Thresholds in eIV. This figure illustrates the net benefit of using PCE alone versus integrated models incorporating PRSCHD and FamHx across actionable risk thresholds. The vertical dashed lines indicate the 7.5% and 10% actionable thresholds. The grey line represents the strategy of no intervention, yielding a net benefit of zero. The black line reflects the strategy of preventing all individuals, which initially provides the highest net benefit but declines due to unnecessary preventive interventions and associated harms or costs in low-risk persons. The red, blue, and green lines represent the net benefit of PCE, PCE + PRSCHD, and PCE + PRSCHD + FamHx, respectively. Across the entire eIV cohort and all major SIRE groups, incorporating PRSCHD and FamHx improved net benefit compared to PCE alone, highlighting the superior clinical utility of these enhanced models for guiding prevention strategies. Abbreviations: CHD: coronary heart disease, eIV: eMERGE IV study, FamHx: family history of CHD, PCE: pooled cohort equations, PRSCHD: polygenic risk score for CHD

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  Figure 5:. Decision Curve Analysis for PCE and Integrated Scores’ Performance Across Self-Identified Race/Ethnicity Groups in eIV. This plot presents the net benefit analysis of the PCE (left panel), PCE and PRSCHD (middle panel), and PCE, PRSCHD, and FamHx (right panel) across actionable risk thresholds in White, Black, and Hispanic/Latino individuals. Between the 7.5% and 10% risk thresholds, PCE demonstrated the highest predictive performance in White individuals, followed by Black individuals, with the lowest performance observed in Hispanic/Latino individuals. Abbreviation: CHD: coronary heart disease, eIV: eMERGE IV study, FamHx: family history of CHD, PCE: pooled cohort equations, PRSCHD: polygenic risk score for CHD