HOT OFF THE PRESS!

Originally published January 4, 2019 as an update to Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 11th edition

Debra L. Beck and Eugene Braunwald, MD

Genomic risk prediction of CAD in 480,000 adults

Early identification of coronary artery disease (CAD) is difficult using traditional risk factors and risk scores. While it is well known that CAD has substantial heritability and a polygenic architecture, genomic risk scores to help predict early CAD have yet to be shown especially effective. In this study, Inouye et al constructed a genomic risk score based on 1.7 million single nucleotide polymorphisms (SNPs) to predict lifetime risk trajectories for CAD.

The researchers developed built a new genomic risk score for CAD (called metaGRS) using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data. The score was based on 3 other genetic risk scores and included 1.7 million genetic variants. They tested the score externally by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank.

For every 1 standard deviation increase in metaGRS the hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73), an association larger than any other externally tested genetic risk score previously published, and higher also than the degree of risk captured using any single conventional risk factor or combination of conventional risk factors. The metaGRS also had a higher C-index for incident CAD than any of the conventional risk factors.

The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. For contrast, the corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications.

Summary

The author concluded that the genomic score developed and evaluated here “substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.”

Comments

In an editorial, Dr. P Natarajan noted that a polygenic risk score is stable from birth, only needs to be performed once (at a current cost of <$100), and can be used to “calculate polygenic risk for virtually any trait.” However, “precision prevention” still relies on the ability to motivate health behavior change, which has proven difficult.

Reference

• 1. M Inouye, G Abraham, CP Nelson, et al: Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention. J Am Coll Cardiol. 72(16): 1883-1893. 2018 Oct 16. 30309464
• 2. P Natarajan: Polygenic Risk Scoring for Coronary Heart Disease: The First Risk Factor. J Am Coll Cardiol. 72(16): 1894-1897. 2018 Oct 16. 30309465

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine features a unique update program by Dr. Braunwald, creating a “living textbook” by featuring twice monthly updates including “Hot off the Press” and Late-Breaking Clinical Trials (links to authors’ presentation slides are also included).

Learn more about Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 11th Edition. Download a free chapter here.