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Genome-wide Polygenic Score Predicts CV Events in Secondary Prevention Population

Key findings

  • Previously, researchers at Massachusetts General Hospital developed a genome-wide polygenic score (GPS) that predicts an individual's risk of coronary artery disease
  • In this study, the GPS predicted major adverse cardiovascular events in a secondary prevention population, patients with high-risk vascular disease who were participating in a clinical trial
  • The GPS did not identify patients who benefit from the medicine tested in the clinical trial (evacetrapib) to prevent secondary cardiovascular events
  • Use of the GPS might allow researchers to enroll "genetically enriched" trial populations that will have significantly higher event rates, allowing for decreased sample size and cost

In 2018, a pioneering study from researchers at Massachusetts General Hospital showed that genome-wide polygenic scores (GPSs) identified people at high risk for five common diseases including coronary artery disease (CAD) and atrial fibrillation. GPSs integrate information from many common DNA variants into a single measure of inherited susceptibility.

Now, Amit V. Khera, MD, MSc, cardiologist and a medical director of the Preventive Genomics Clinic, Connor A. Emdin, PhD, of the Center for Genomic Medicine at Mass General, Minxiang Wang, PhD, of the Broad Institute, and colleagues have extended that research, showing that the GPS for CAD is also useful in a secondary prevention population: it predicted major adverse cardiovascular events among patients with high-risk vascular disease. They report their findings in a research letter in Circulation: Genomic and Precision Medicine.

Study Design

The team used data from the ACCELERATE trial (n=12,092), published in the New England Journal of Medicine, which determined that evacetrapib, a cholesteryl ester transfer protein inhibitor, did not reduce the risk of major cardiovascular events compared with placebo among patients with preexisting vascular disease.

Previously, in a nested case–control substudy of ACCELERATE published in Circulation, the trial investigators had genotyped 1,437 patients who had a major cardiovascular event during follow-up (cardiovascular-related death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and 1,547 matched controls.

In the new analysis, the researchers calculated the previously validated GPS for CAD, composed of 6.6 million genetic variants, for each of the 2,984 participants in the ACCELERATE genetics substudy. They classified the patients into GPS quintiles.

Association of GPS with Major Cardiovascular Events

The researchers found:

  • After adjustment for age, sex and five principal components of ancestry, patients in the highest GPS quintile were at 60% greater risk of a major cardiovascular event than those in the lowest quintile (OR, 1.60; 95% CI, 1.35–1.89; P <.0001)
  • After additional adjustment for cardiovascular risk factors, the highest GPS quintile was associated with a 52% greater risk of a cardiovascular event (OR, 1.52; 95% CI, 1.28–1.80; P < .0001)

GPS and Efficacy of Evacetrapib

In the case–control study, 1,494 patients had been randomly assigned to receive evacetrapib. The researchers assessed whether the GPS could identify a subgroup of individuals who derived benefit. However, overall and within each GPS quintile, there was no evidence that evacetrapib was superior to placebo in reducing major cardiovascular events.

Research Implications

In the cardiology field, it's expensive to test therapeutic hypotheses because large samples are needed to detect high enough rates of cardiovascular events. Use of the GPS might allow researchers to enroll "genetically enriched" trial populations that will have significantly higher event rates, allowing for decreased sample size and cost.

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