Integrating genomic and nongenomic risk for coronary artery disease

项目总结 候选人。Akl Fahed，医学博士，公共卫生硕士，是内科、心脏病学和 马萨诸塞州综合医院(MGH)工作人员的介入心脏病学。他也是一名 他在哈佛医学院(HMS)获得医学博士学位，并在哈佛/麻省理工学院博士后学院获得博士后学位。他 在培训的每个阶段都有科学承诺和生产力的跟踪记录，并已发布了26 在过去的十年里，心血管遗传学方面的论文--包括18篇第一作者。他现在寻求 在之前的心脏病学和人类遗传学培训的基础上扩展，以促进专注于改进的职业生涯 预防和治疗冠心病。导师、培训活动和环境。Dr。 法赫德将在帕特里克·埃利诺博士的指导下，在麻省理工学院和布罗德医院执行拟议的工作， 内科医生、科学家和心血管遗传学的国际领导者，在 Mentorship和PraDeep Natarajan博士，他是一位在冠状动脉疾病遗传学方面有专长的内科科学家 和预防。这一指导团队将得到高度承诺和有成就的顾问的补充 彼得·克拉夫特博士和海蒂·雷姆博士委员会。正式的课程工作将加强多学科的 体验式学习努力获得计算生物学、预测分析和责任感方面的必要技能 研究行为。研究。冠状动脉疾病(CAD)仍然是全球主要的死亡原因 尽管改进了对风险因素的治疗。基因组风险提供了及早认识和 在危险因素发作之前进行有针对性的干预，但其使用有两个关键障碍：1)没有 将基因组和非基因组因素结合起来预测冠心病绝对风险的单一模型，以及2)存在 基因组风险预测在非欧洲血统中表现不佳。为了解决这些知识差距，PI 我将首先开发和验证CAD的基因组风险模型，该模型结合单基因、多基因和体细胞 使用46万个欧洲血统个体的数据进行变异。其次，他将开发和验证一个 结合基因组和非基因组(血压、胆固醇、血液)的CAD综合风险模型 糖、运动、体重、饮食和吸烟)是欧洲血统个体的风险驱动因素。第三，他将优化 这个模型适用于非洲人、南亚人、东亚人和西班牙人祖先，使用了150,000个数据 来自几个多种族研究的个人。成功完成拟议的研究将为 向个人及其照顾者披露CAD综合风险信息的科学基础 促进有针对性的干预。此外，该提案将为私家侦探提供关键培训，以促进其 过渡到心血管遗传学的独立内科研究员，所产生的数据将有助于 作为未来R01应用的基础。

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.