Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention
Loos, Ruth JF
Angelantonio, Emanuele Di
for The UK Biobank CardioMetabolic Consortium CHD Working Group
Journal of the American College of Cardiology
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Inouye, M., Abraham, G., Nelson, C., Wood, A., Sweeting, M., Dudbridge, F., Lai, F., et al. (2018). Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention. Journal of the American College of Cardiology https://doi.org/10.1101/250712
<h4>Background</h4> Coronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention. <h4>Methods</h4> 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, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank. <h4>Findings</h4> In UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution. <h4>Interpretation</h4> Recent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification. <h4>Funding</h4> National Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.
Genomic Risk Prediction, Coronary Artery Disease, Primary Prevention
This study was supported by funding from National Health and Medical Research Council (NHMRC) grant APP1062227. Supported in part by the Victorian Government’s OIS Program. M.I. was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). G.A. was supported by an NHMRC Early Career Fellowship (no. 1090462). N.J.S., C.P.N. and B.K. are supported by the British Heart Foundation and N.J.S. is a NIHR Senior Investigator. R.S.P. is supported by the British Heart Foundation (FS/14/76/30933). The MRC/BHF Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council [MR/L003120/1], British Heart Foundation [RG/13/13/30194], and UK National Institute for Health Research Cambridge Biomedical Research Centre. J.D. is a British Heart Foundation Professor and NIHR Senior Investigator.
Medical Research Council (G0701619)
Medical Research Council (MR/S003746/1)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
External DOI: https://doi.org/10.1101/250712
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284949