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Better Guidelines Needed to Distinguish Individuals at Elevated Polygenic Risk of CAD

Key findings

  • In this study, a genome-wide coronary artery disease (CAD) polygenic risk score (PRS) was calculated for 47,108 individuals based on genetic and clinical data maintained by three large health care systems
  • Across the systems, the CAD PRS demonstrated robust associations with prevalent CAD
  • Polygenic risk for CAD was not fully captured by guideline-based clinical risk algorithms
  • 4% of primary prevention patients were estimated to be newly suitable for a statin prescription if polygenic risk were used as a CAD "risk enhancer" to inform clinical decision-making

Using published data on more than six million common genetic variants, researchers at Massachusetts General Hospital recently developed a genome-wide polygenic risk score (PRS) that quantifies inherited susceptibility to coronary artery disease (CAD).

Writing in the Journal of the American College of CardiologyKrishna G. Aragam, MD, MS, preventive cardiologist, and Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center at Massachusetts General Hospital, and colleagues now report that the Mass General developed CAD PRS is additive to conventional paradigms for assessing clinical risk—and its use could alter the management of primary prevention patient cohorts.

Study Design

The researchers analyzed genetic and clinical data on 47,108 individuals, average age 60, from biobanks maintained by Mass General and two other large health care systems in the eastern U.S. The CAD PRS was calculated for each person.

Within the larger cohort, the team analyzed 20,628 individuals without known atherosclerotic cardiovascular disease (CAD, peripheral artery disease and/or cerebral atherosclerosis). They calculated the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) using the Pooled Cohort Equations of the American College of Cardiology and American Heart Association.

The researchers determined whether each individual in the primary prevention patient cohort was eligible for statin therapy according to 2018 guidelines of the ACC/AHA and, separately, according to 2016 guidelines of the U.S. Preventive Services Task Force (USPSTF).

Validation of the PRS

Across the entire study population, the CAD PRS strongly associated with prevalent CAD (OR, 1.42 per 1 standard deviation increase in the PRS; 95% CI, 1.38–1.46; P < .0001). Effect estimates were consistent across the three biobanks.

Individuals in the top 20% of the PRS distribution were at 1.9-fold higher odds of CAD (compared with the bottom 80%) and those in the top 5% were at 2.3-fold higher odds (compared with the bottom 95%).

Statin Eligibility in the Primary Prevention Cohort

Pooled cohort equations—Similar proportions of patients in the top 20% versus the remaining 80% of the PRS distribution were classified as "low" (43% vs. 41%), "borderline" (8% vs. 9%), "intermediate" (27% vs. 27%) or "high" (22% vs. 23%) risk of ASCVD by the Pooled Cohort Equations.

Guidelines—Similar proportions of individuals in the top 20% versus the bottom 80% of the CAD PRS distribution met ACC/AHA criteria (46% vs. 47%; P = NS) and/or USPSTF criteria (44% vs. 44%; P = NS) for statin initiation.

These findings suggested that contemporary approaches to clinical risk assessment for the primary prevention of CAD do not distinguish those at high polygenic risk from the rest of the population.

CAD PRS as a Risk-enhancing Factor

The 2018 ACC/AHA guidelines recommend considering "risk-enhancing factors" to guide statin initiation in patients without ASCVD, diabetes or severe hypercholesterolemia who are at borderline or intermediate 10-year risk of ASCVD according to the Pooled Cohort Equations. Risk-enhancing factors are those that independently associate with CAD and confer a near twofold risk of disease.

Because the investigators observed 1.9-fold greater odds of CAD among individuals in the top 20% of the CAD PRS, they conducted a post hoc analysis to explore statin prescription rates. They found:

  • 16,002 individuals in the study were without ASCVD, diabetes or severe hypercholesterolemia
  • 5,890 of those had a borderline or intermediate 10-year risk of ASCVD
  • 987 were in the top 20% of the CAD PRS
  • 652 (4% of 16,002) did not have a statin prescription

Applying the Findings to Practice

Considering a CAD PRS may influence the management of a subset of middle-aged primary prevention patients when clinical uncertainty remains after reviewing standard guidelines.

However, the unique strength of a CAD PRS is that it can be assessed early in life—and it doesn't change. Earlier knowledge of a PRS may prompt more timely initiation of strategies to prevent CAD.

higher odds of prevalent coronary artery disease for individuals in the top 20% of polygenic risk score distribution

higher odds of prevalent coronary artery disease for individuals in the top 5% of polygenic risk score distribution

of primary prevention patients were identified as newly suitable for a statin when the polygenic risk score was factored into decision-making

Learn more about the Cardiovascular Disease Prevention Center at Mass General

Refer a patient to the Corrigan Minehan Heart Center

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