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Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults

2018; Elsevier BV; Volume: 72; Issue: 16 Linguagem: Inglês

10.1016/j.jacc.2018.07.079

1558-3597

Michael Inouye, Gad Abraham, Christopher P. Nelson, Angela Wood, Michael Sweeting, Frank Dudbridge, Florence Lai, Stephen Kaptoge, Marta Brożyńska, Tingting Wang, Shu Ye, Tom R. Webb, Martin K. Rutter, Ioanna Tzoulaki, Riyaz Patel, Ruth J. F. Loos, Bernard Keavney, Harry Hemingway, John R. Thompson, Hugh Watkins, Panos Deloukas, Emanuele Di Angelantonio, Adam S. Butterworth, John Danesh, Nilesh J. Samani,

BRCA gene mutations in cancer

Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both 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. The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. 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%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. 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.