Combining Genetics with Lipid and Inflammatory Biomarkers to Predict Coronary Artery Disease Risk

Abstract

PAPER 1 ABSTRACT BACKGROUND: Coronary artery disease (CAD) polygenic risk score (PRS), low-density-lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp(a)), and high-sensitivity C-reactive protein (hsCRP) are biomarkers that predict CAD. It is unclear whether integrating genomics with lipid and inflammatory biomarkers could complement traditional risk scores in identifying people at risk of CAD. OBJECTIVES: This study assesses the predictive value of CAD PRS, LDL-C, Lp(a), and hsCRP for incident CAD across different age and sex groups. METHODS: Participants (n = 215,695) from the UK Biobank aged 40 to 69 years with baseline CAD PRS, LDL-C, Lp(a), and hsCRP values were followed for 12 years to assess the incidence of CAD. We evaluated a multivariable-adjusted Cox model that included all 4 biomarkers, net reclassification index, C-statistics, and population attributable risk across different age and sex groups. RESULTS: Over a 12-year follow-up, 4,721 men and 2,425 women developed CAD. The HRs for incident CAD associated with each biomarker elevation were 1.79 (95% CI: 1.70-1.89) for CAD PRS, 1.60 (95% CI: 1.48-1.66) for LDL-C, 1.20 (95% CI: 1.12-1.29) for Lp(a), and 1.64 (95% CI: 1.57-1.72) for hsCRP. CAD PRS demonstrated a stronger association in men (HR per SD: 1.49; 95% CI: 1.45-1.54) than women (HR per SD: 1.37; 95% CI: 1.31-1.44; P-interaction # 0.001). All biomarkers conferred greater HRs at younger ages (P 0.0001). Individuals with all biomarkers elevated had a 4.65-fold increased risk of CAD compared with those with no elevated biomarkers. A combined 4-biomarker model had a higher C-statistic of 0.753 compared with the pooled cohort equations (C-statistic of 0.740). The C-statistic of the combined 4-biomarker model was also higher in younger individuals in both sexes and yielded a 32.0% continuous net reclassification index when compared with the pooled cohort equations. CONCLUSIONS CAD PRS, LDL-C, hsCRP, and Lp(a) show independent age- and sex-specific associations with CAD. Measuring all 4 biomarkers may improve midlife CAD risk prediction for both male and female patients. (JACC. 2026) © 2026 by the American College of Cardiology Foundation. PAPER 2 ABSTRACT BACKGROUND: Many patients develop coronary artery disease (CAD) despite being free from standard modifiable risk factors (SMuRFlesss), including diabetes, smoking, hyperlipidemia, and hypertension. Prevention beyond traditional risk factors is needed for primary prevention of SMuRFless individuals. Coronary artery disease polygenic risk score (CAD PRS), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (hs-CRP) are residual blood biomarkers that predict CAD. This research aimed to investigate the utility of inflammatory, genetic, and Lp(a) residual biomarkers and the prediction of CAD in SMuRFless participants of the UK Biobank (UKB). METHODS: Baseline measurements of biomarkers hs-CRP, CAD PRS, and Lp(a) were obtained from 40,723 healthy participants of the UKB, a prospective cohort study enrolling individuals ages 40–69 years from 2006–2010, who were SMURFless at enrollment and were followed for a median of 13.7 (12.0–14.4) years for incident CAD and major adverse cardiovascular events (MACE). A Cox model, adjusted for age, sex, estimated glomerular filtration fraction, body mass index, systolic blood pressure, Townsend deprivation index and the first 10 ancestral principal components (only in a model with CAD PRS), was calculated across quintiles of biomarkers. Hazards ratios were also calculated according to commonly used clinical thresholds and continuous scales of hs-CRP, CAD PRS and Lp(a). Additionally, a 13.7-year adjusted cumulative incidence curve for each biomarker and joint effects analyses between two biomarkers (CAD PRS and Lp(a), CAD PRS and hs-CRP, Lp(a) and hs-CRP), adjusted for age and sex, were plotted for incident CAD and MACE. RESULTS: Over a follow-up of 13.7 years, 521 of 40723 (1.00%) developed incident CAD. Median hs-CRP and Lp(a) and mean CAD PRS were higher among SMuRFless individuals with incident CAD compared to SMuRFless individuals with no CAD (median hs-CRP 1.22 vs. 0.88 mg/L, P.001, mean CAD PRS 0.40 vs -0.01 standardized units, P.001, median Lp(a) 20.1 vs. 17.0 nmol/L, P.001). Compared to the lowest quintile, the HR in an adjusted Cox model for incident CAD for quintiles 2 to 5 were associated with increasing HRs for hs-CRP (1.21, 1.13, 1.49, and 1.58), CAD PRS (1.56, 1.80, 2.62, 4.00) and for Lp(a) (0.91, 0.86, 0.90, 1.23). The risk of CAD increased by 12% (HR 1.12, 95% CI 1.03–1.23), 40% (1.40, 95% CI 1.31–1.49), and 5% (HR 1.05, 95% CI 1.01–1.12%) for each increasing quintile in hs-CRP, CAD PRS, and Lp(a), respectively. Joint effect analysis showed independent contribution of each biomarker to incident CAD, with the highest risk observed when there was a joint increase in biomarker in the fifth quintile. Results remain consistent for our secondary outcome MACE but not for Lp(a). CONCLUSION: Among SMuRFless individuals, elevated levels of hs-CRP, CAD PRS, and Lp(a) were associated with incident CAD, suggesting these biomarkers can aid in clinical stratification of SMuRless individuals with otherwise silent elevated risk.