Limitations of Contemporary Guidelines for Managing Patients at High Genetic Risk of Coronary Artery Disease

Abstract

Background: Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by conventional paradigms for assessing clinical cardiovascular risk remains unclear.

Objectives: This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention.

Methods: A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy.

Results: Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p < 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p < 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor.

Conclusions: Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.

Keywords: coronary artery disease; genetic risk; primary prevention; statin.

Figure 1.. Association of coronary artery disease polygenic risk score with coronary artery disease across three healthcare systems.

Logistic regression was used to test the association of a one standard deviation increase in a genome-wide CAD PRS with prevalent CAD in the Partners Biobank, Penn Medicine Biobank, and the Mt. Sinai BioMe Biobank. Logistic regression models were adjusted for age, sex, and the first 5 principal components of ancestry. In the Partners Biobank, an additional adjustment for genotyping array was included. Principal components of ancestry were based on observed genotypic differences across subpopulations (i.e., race or ethnicity) within each overall study. Fixed-effects meta-analysis was used to combine results across cohorts (P_{heterogeneity}=0.57). Cohort-specific participant numbers and CAD case counts are displayed. CAD case counts represent the sum total of disease at baseline and incident disease. Abbreviations: CAD=coronary artery disease; CI=confidence interval; OR=odds ratio; PRS=polygenic risk score; SD=standard deviation.

Figure 2.. Guideline-based clinical risk estimation and statin-eligibility by strata of CAD PRS.

Among primary prevention patients without atherosclerotic cardiovascular disease and with available clinical data (N=20,628), individuals in the Top 20% versus the Bottom 80% of the CAD PRS were compared with respect to: (A) Clinical risk as defined by the ACC/AHA Pooled Cohort Equations (PCE); and (B) Statin-eligibility as defined by the 2018 ACC/AHA Guidelines on Blood Cholesterol Management and the 2016 USPSTF guidelines for primary prevention statin therapy. Abbreviations: ACC=American College of Cardiology; AHA=American Heart Association; CAD=coronary artery disease; PRS=polygenic risk score; USPSTF=United States Preventive Services Task Force.

Figure 3.. Management patterns by strata of CAD PRS.

Among primary prevention patients without atherosclerotic cardiovascular disease (N=33,251), individuals in the Top 20% versus the Bottom 80% of the CAD PRS were compared with respect to rates of statin prescriptions (Statin RX), and attainment of LDL-C < 100mg/dl. Abbreviations: CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; PRS=polygenic risk score.

Central Illustration.. Conventional clinical parameters do not distinguish patients at high polygenic risk for coronary artery disease.

Abbreviations: ACC=American College of Cardiology; AHA=American Heart Association; CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; PRS=polygenic risk score; USPSTF=United States Preventive Services Task Force.