Discovery and Application of Germline and Somatic Mutations for Risk Prediction and Personalized Therapy to Prevent Recurrent Myocardial Infarction

种系和体细胞突变的发现和应用，用于风险预测和个性化治疗，以预防复发性心肌梗死

• 批准号: 10630122
• 负责人: Nicholas Marston
• 金额: $ 12.96万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630122
• 关键词: Adult; Applied Genetics; Atherosclerosis; Award; Biological; Birth; Cardiology; Cardiovascular Diseases; Cardiovascular system; Caring; Chairperson; Circulation; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Computational Biology; Coronary Arteriosclerosis; Coronary heart disease; Data; Data Set; Decision Making; Dedications; Development; Disease; Educational workshop; Epidemiologist; Event; Faculty; Foundations; Funding; Genes; Genetic; Genetic Databases; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genotype; Germ-Line Mutation; Goals; Hematopoiesis; Hospitals; Hypertension; Individual; Inflammation; Large-Scale Sequencing; Lead; Learning; Lipids; Literature; Manuscripts; Medicine; Mentorship; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; National Research Service Awards; Oral; Pathway interactions; Patient Selection; Patients; Play; Population; Prevention; Prevention therapy; Primary Prevention; Public Health Schools; Publishing; Recurrence; Recurrence Score; Research; Research Personnel; Risk Marker; Role; Rupture; Science; Secondary Prevention; Somatic Mutation; Teaching Hospitals; Testing; Therapeutic; Thrombosis; Thrombus; Time; Training; Variant; Vascular remodeling; Woman; Work; clinical application; data curation; data management; design; exome sequencing; experience; genetic predictors; genetic variant; genome wide association study; genome-wide; high risk; improved; individualized medicine; insight; medical schools; mortality; novel; personalized medicine; polygenic risk score; prevent; randomized, clinical trials; risk prediction; symposium

Project Summary/Abstract Despite significant advances in secondary prevention, recurrent myocardial infarction (MI) remains a major cause of morbidity and mortality. In the U.S., nearly 1 million adults have an MI each year, approximately 1/3 of which are recurrent. Patients surviving their first MI are at a high risk of recurrent events. In those who do develop recurrent MI, the annual mortality rate increases to 10%, two-fold higher than after their first MI. While much work has been done to identify common genetic variation for incident coronary artery disease, there is a large gap in the literature as to what variants contribute to recurrent MI. While overlap likely exists, there are distinct biological features between the development of atherosclerosis and recurrent MI. In Dr. Marston’s preliminary work, he tested a validated incident CAD genome-wide polygenic risk score in a post-MI population and found that it did not predict recurrent MI. This finding formed his central hypothesis that genetic predictors for recurrent MI differ from those that predict incident CAD. Until recently, datasets did not exist to test this hypothesis. However, large amounts of genotyped and sequenced data from randomized clinical trials in post-MI patients are now available, allowing both discovery and clinical application of germline and somatic mutations associated with recurrent MI. In this proposal, Dr. Marston will leverage 9 cardiovascular clinical trials from the TIMI Study Group to test his hypothesis in three specific aims. First, Dr. Marston will define the role of common genetic variation and develop a polygenic risk score for predicting recurrent MI using 14K cases of recurrent MI and 69K MI controls. Novel variants for recurrent MI will be identified through large-scale genome-wide association studies and validated for their ability to predict risk in patients following their first MI. Second, Dr. Marston will determine whether rare genetic variation or clonal hematopoiesis is associated with recurrent MI using exome sequencing data in 9K recurrent MI cases and 39K MI controls. Third, Dr. Marston will use randomized clinical trial data to test for gene x treatment interactions across 5 secondary prevention therapies with a polygenic risk score and across 2 secondary prevention therapies with CHIP. The presence of a gene x treatment interaction can be used to inform therapeutic decision making and tailored therapy. This work will take place in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, a core teaching hospital of Harvard Medical School. Dr. Marston will perform the research under the mentorship of Dr. Marc Sabatine, Chairman of the TIMI Study Group, and Dr. Patrick Ellinor, Director of the Cardiovascular Disease Initiative at the Broad Institute. Dr. Marston’s goal is to become a genetic epidemiologist and clinical trialist with the ability to build large important datasets and use state of the art computational approaches to identify novel insights into the prevention and treatment of CAD. He is dedicated to becoming an independent investigator and using his K08 work as a foundation for an R01, in which he will apply genetic risk markers to improve clinical trial design and optimize precision in cardiovascular care.

项目总结/文摘

项目成果

Risk factors for type 2 MI: the usual suspects or guilt by association?

2 型心肌梗死的危险因素：通常的嫌疑人还是关联罪？

• DOI: 10.1093/eurheartj/ehab707
• 发表时间: 2022
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: O'Donoghue,MichelleL;Marston,NicholasA
• 通讯作者: Marston,NicholasA

Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.

• DOI: 10.1161/circulationaha.119.043805
• 发表时间: 2020-02-25
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Marston NA;Kamanu FK;Nordio F;Gurmu Y;Roselli C;Sever PS;Pedersen TR;Keech AC;Wang H;Lira Pineda A;Giugliano RP;Lubitz SA;Ellinor PT;Sabatine MS;Ruff CT
• 通讯作者: Ruff CT

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

心脏代谢疾病患者中缺血性中风的新型遗传风险评分的临床应用。

• DOI: 10.1161/circulationaha.120.051927
• 发表时间: 2021-02-02
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Marston NA;Patel PN;Kamanu FK;Nordio F;Melloni GM;Roselli C;Gurmu Y;Weng LC;Bonaca MP;Giugliano RP;Scirica BM;O'Donoghue ML;Cannon CP;Anderson CD;Bhatt DL;Gabriel Steg P;Cohen M;Storey RF;Sever P;Keech AC;Raz I;Mosenzon O;Antman EM;Braunwald E;Ellinor PT;Lubitz SA;Sabatine MS;Ruff CT
• 通讯作者: Ruff CT

Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials.

• DOI: 10.1016/s0140-6736(20)32332-1
• 发表时间: 2020-11-21
• 期刊: Lancet (London, England)
• 作者: Gencer B;Marston NA;Im K;Cannon CP;Sever P;Keech A;Braunwald E;Giugliano RP;Sabatine MS
• 通讯作者: Sabatine MS

Predictive Utility of a Coronary Artery Disease Polygenic Risk Score in Primary Prevention.

• DOI: 10.1001/jamacardio.2022.4466
• 发表时间: 2022-12
• 期刊: JAMA cardiology
• 影响因子: 24
• 作者: N. Marston;J. Pirruccello;G. Melloni;S. Koyama;Frederick K. Kamanu;L. Weng;C. Roselli;Y. Kamatani;I. Komuro;K. Aragam;A. Butterworth;K. Ito;S. Lubitz;P. Ellinor;M. Sabatine;C. Ruff