Author + information
- Received June 19, 2018
- Revision received July 23, 2018
- Accepted July 24, 2018
- Published online October 8, 2018.
- Michael Inouye, PhDa,b,c,d,e,∗∗ ( )(, )@minouye271@BakerResearchAu@uniofleicester,
- Gad Abraham, PhDa,b,c,d,∗∗∗ (, )
- Christopher P. Nelson, PhDf,
- Angela M. Wood, PhDc,
- Michael J. Sweeting, PhDc,
- Frank Dudbridge, PhDc,g,
- Florence Y. Lai, MPhilf,
- Stephen Kaptoge, PhDc,h,
- Marta Brozynska, PhDa,b,c,
- Tingting Wang, PhDa,b,c,
- Shu Ye, MD, PhDf,
- Thomas R. Webb, PhDf,
- Martin K. Rutter, MDi,j,
- Ioanna Tzoulaki, PhDk,l,
- Riyaz S. Patel, MDm,n,
- Ruth J.F. Loos, PhDo,
- Bernard Keavney, MDp,q,
- Harry Hemingway, MDr,
- John Thompson, PhDg,
- Hugh Watkins, MD, PhDs,t,
- Panos Deloukas, PhDu,
- Emanuele Di Angelantonio, MD, PhDc,h,
- Adam S. Butterworth, PhDc,h,
- John Danesh, DPhilc,h,v,
- Nilesh J. Samani, MDf,∗∗∗∗ (, )
- for the UK Biobank CardioMetabolic Consortium CHD Working Group
- aCambridge Baker Systems Genomics Initiative, Melbourne, Victoria, Australia, and Cambridge, United Kingdom
- bBaker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- cMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- dDepartment of Clinical Pathology and School of BioSciences, University of Melbourne, Parkville, Victoria, Australia
- eThe Alan Turing Institute, London, United Kingdom
- fDepartment of Cardiovascular Sciences and NIHR Leicester Biomedical Centre, University of Leicester, Leicester, United Kingdom
- gDepartment of Health Sciences, University of Leicester, Leicester, United Kingdom
- hNational Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, United Kingdom
- iDivision of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- jManchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
- kDepartment of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
- lDepartment of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece
- mInstitute of Cardiovascular Sciences, University College London, London, United Kingdom
- nBarts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom
- oCharles Bronfman Institute for Personalized Medicine, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- pDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
- qManchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
- rThe Farr Institute of Health Informatics Research and the National Institute for Health Research, Biomedical Research Centre, University College London, London, United Kingdom
- sDivision of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
- tThe Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
- uWilliam Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- vWellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
- ↵∗Address for correspondence:
Dr. Michael Inouye, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
- ↵∗∗Dr. Gad Abraham, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
- ↵∗∗∗Dr. Nilesh J. Samani, Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield General Hospital, Leicester LE3 9QP, United Kingdom.
Background 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.
Objectives This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention.
Methods 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.
Results 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.
Conclusions 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.
↵∗ Drs. Inouye, Abraham, and Samani contributed equally to this work.
This study was supported by funding from National Health and Medical Research Council (NHMRC) grant APP1062227; and was supported in part by the Victorian Government’s OIS Program. Dr. Inouye was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). Dr. Abraham was supported by an NHMRC Early Career Fellowship (no. 1090462). Drs. Nelson, Keavney, and Samani are supported by the British Heart Foundation, and Dr. Samani is an NIHR Senior Investigator. Dr. Rutter has received honoraria and consulting fees from Novo Nordisk, Ascensia, Cell Catapult, and Roche Diabetes Care. Dr. Patel 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. Dr. Butterworth has received grant support from Merck, Novartis, Pfizer, Biogen, Bioverativ, and AstraZeneca; and serves as a consultant to Novartis. Dr. Danesh is a British Heart Foundation Professor and NIHR Senior Investigator. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Pradeep Natarajan, MD, MMSc, served as Guest Editor for this paper.
- Received June 19, 2018.
- Revision received July 23, 2018.
- Accepted July 24, 2018.
- 2018 The Authors