Integrating genomic and nongenomic risk for coronary artery disease

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PROJECT SUMMARY Candidate. Akl Fahed, MD, MPH is a board-certified physician in internal medicine, cardiology, and interventional cardiology on staff at the Massachusetts General Hospital (MGH). He is also instructor in medicine at Harvard Medical School (HMS) and postdoctoral scholar at the Broad Institute of Harvard/MIT. He has a track record of scientific commitment and productivity at each phase of training and has published 26 papers – including 18 as first author – in cardiovascular genetics over the past decade. He now seeks to expand upon previous training in cardiology and human genetics to catalyze a career focused on improving prevention and treatment of coronary artery disease. Mentorship, Training Activities, and Environment. Dr. Fahed will perform the proposed work at MGH and the Broad under the mentorship of Dr. Patrick Ellinor, a physician-scientist and international leader in cardiovascular genetics with an outstanding track record for mentorship and Dr. Pradeep Natarajan, a physician-scientist with expertise in coronary artery disease genetics and prevention. This mentorship team will be complemented by a highly committed and accomplished Advisory Committee of Drs. Peter Kraft and Heidi Rehm. Formal coursework will enhance a multi-disciplinary experiential learning effort to gain requisite skills in computational biology, predictive analytics, and responsible research conduct. Research. Coronary artery disease (CAD) remains a leading cause of death worldwide despite improved treatment of risk factors. Genomic risk provides opportunity for earlier recognition and targeted intervention prior to onset of risk factors, but there are two key barriers for its use: 1) There is no single model that combines genomic and nongenomic factors to predict absolute risk of CAD, and 2) existing genomic risk prediction underperforms in non-European ancestries. To address these knowledge gaps, the PI will first develop and validate a genomic risk model for CAD that combines monogenic, polygenic, and somatic variation using data on >460,000 European ancestry individuals. Second, he will develop and validate an integrated risk model for CAD that combines genomic and nongenomic (blood pressure, cholesterol, blood sugar, exercise, weight, diet, and smoking) risk drivers in European ancestry individuals. Third, he will optimize this model for individuals of African, South Asian, East Asian and Hispanic ancestries using data on >150,000 individuals from several multiethnic studies. Successful completion of the proposed studies will lay the scientific foundation for disclosing integrated risk information for CAD to individuals and their caregivers to facilitate targeted interventions. Furthermore, the proposal will provide key training of the PI to facilitate his transition to an independent physician investigator in cardiovascular genetics and the data generated will serve as the basis for a future R01 application.