Genomic variants associated with angina and health status outcome after MI

与心绞痛和心肌梗死后健康状况结果相关的基因组变异

• 批准号: 8818197
• 负责人: SHARON CRESCI
• 金额: $ 65.25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-27 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818197
• 关键词: Acute myocardial infarction; Address; Admission activity; Adult; Alleles; Angioplasty; Attention; Bypass; Cardiovascular system; Caring; Center for Translational Science Activities; Chest Pain; Chronic Disease; Clinical Trials; Control Groups; Coronary Arteriosclerosis; Counseling; Data; Diabetes Mellitus; Diagnostic Procedure; Disease; Enrollment; Event; Foundations; Funding; Genes; Genetic; Genomics; Genotype; Goals; Growth; Health; Health Status; Homozygote; Hospitals; Hour; Individual; Individual Differences; Investigation; Measurement; Medical; Mental Depression; Methods; Modeling; Molecular Biology; Myocardial Infarction; Outcome; Outcome Study; Outcomes Research; Pain Threshold; Patient Care; Patients; Perception; Pharmacogenomics; Pilot Projects; Population; Prospective Studies; Province; Qualifying; Quality of life; Questionnaires; Research; Research Personnel; Risk; Running; Scanning; Smoker; Staging; Strategic Planning; Symptoms; Testing; Time; Translating; United States; United States National Institutes of Health; Validation; Variant; Visit; adjudicate; base; cohort; cost; design; genetic variant; improved; mortality; non-genetic; non-genomic; novel; patient oriented; personalized care; pleiotropism; predictive modeling; prevent; productivity loss; public health relevance; response; screening; smoking cessation; symptom management; tool

 DESCRIPTION (provided by applicant): Little attention has been paid to patient-centered health status outcomes such as angina, depression, and worse quality of life after myocardial infarction (MI) but these are often the factors that patients care about the most. More than 10 million people in the US suffer from angina and approximately 500,000 new cases occur each year at an estimated cost of $20 billion dollars annually. We propose to identify novel genomic and non- genomic factors that contribute to inter-individual variation in post-MI angina and health status outcomes by using the TRIUMPH population, and NIH-funded cohort with exquisite disease-specific health status assessments at admission, and 1-month, 6-months and 1-year post-MI, along with adjudicated 1-year major adverse cardiovascular events and 5-year mortality. The study group is particularly well qualified to perform this research, having expertis in genomics, pharmacogenomics, patient screening and risk profiling, acute MI management, clinical trials, outcomes research, and statistical genomics. Collectively, we will address the following Aims: AIM 1. Identification and Validation of Novel Genomic and Non-Genomic Factors Contributing to Inter-individual Variation in Post-MI Angina There will be two ongoing stages of this AIM. The first is to continue to comprehensively identify genomic and non-genomic factors contributing to post-MI angina in a focused and sequential way. We propose to use novel statistical approaches including SMART-scan, growth curve estimation, and pleiotropy and collapsing methods to achieve this AIM. The second stage of this AIM is to validate the genomic predictors we have identified in the initial funding cycle and to continue thi validation for all newly identified genomic variants. We intend to use multiple validation cohorts to validate and extend our findings, including the INFORM, PREMIER, BARI 2D and GENESIS-PRAXY study. AIM 2. Pilot Study to Test Genotype-guided Post-MI Therapy Aimed at Decreasing Post-MI Angina We propose to show the feasibility of incorporating genotype-guided therapy into post-MI therapy using the CHRNA5 rs16969968 variant as our pilot case and using a novel prognostic modeling tool (PRISMTM) which allows multivariable models to be run with patient-specific data to predict post-MI outcomes. This pilot study will lay the foundation for personalized, genotype-guided, post-MI therapy aimed at decreasing angina symptoms and improving the quality of life for post-MI patients. The successful execution of these AIMs will enable us to help implement the NINRs strategic plan and address several of the NINR's key themes, including personalized health strategies toward symptom management, improving quality of life for individuals with chronic diseases, and promoting health and preventing illness. In summary, we will use cutting edge experimental, statistical, and diagnostic methods to identify genomic and non-genomic factors associated with post-MI angina and initiate the first step towards personalized post-MI care with the overarching goal of reducing angina symptoms and improving outcomes.

 描述(申请人提供)：很少关注以患者为中心的健康状况结果，如心绞痛、抑郁和心肌梗塞(MI)后较差的生活质量，但这些通常是患者最关心的因素。美国有1000多万人患有心绞痛，每年约有50万新病例发生，估计每年的成本为200亿美元。我们建议通过使用凯旋人群和NIH资助的队列，在入院时、心肌梗塞后1个月、6个月和1年进行精确的疾病特定健康状况评估，以及判定1年主要不良心血管事件和5年死亡率，来识别导致心肌梗死后心绞痛和健康状况结果个体间差异的新的基因组和非基因组因素。研究小组特别有资格进行这项研究，他们在基因组学、药物基因组学、患者筛查和风险分析、急性心肌梗死管理、临床试验、结果研究和统计基因组学方面拥有专业知识。总的来说，我们将致力于以下目标：目标1.识别和验证导致心肌梗死后心绞痛个体间差异的新的基因组和非基因组因素。第一是继续有重点、有序贯地全面识别导致心肌梗死后心绞痛的基因组和非基因组因素。我们建议使用新的统计方法，包括智能扫描、增长曲线估计、多效性和塌陷方法来实现这一目标。这一目标的第二阶段是验证我们在最初的资金周期中确定的基因组预测因子，并继续对所有新确定的基因组变异进行验证。我们打算使用多个验证队列来验证和扩展我们的发现，包括INFORM、Premier、BARI 2D和Genesis-PRAXY研究。目的2.旨在测试旨在减少心肌梗死后心绞痛的基因引导的心肌梗死后治疗的初步研究我们建议以CHRNA5 rs16969968变异作为我们的试点病例，并使用一种新的预后建模工具(PrismTM)来显示将基因引导的治疗纳入心肌梗死后治疗的可行性，该工具允许用患者特定的数据运行多变量模型来预测心肌梗死后的结果。这项先导性研究将为个人化、基因指导的心肌梗死后治疗奠定基础，旨在减轻心绞痛症状，提高心肌梗死后患者的生活质量。这些目标的成功实现将使我们能够帮助实施NINRS战略计划，并解决NINR的几个关键主题，包括针对症状管理的个性化健康战略，提高慢性病患者的生活质量，以及促进健康和预防疾病。 总之，我们将使用最先进的实验、统计和诊断方法来确定与心肌梗死后心绞痛相关的基因组和非基因组因素，并启动个性化心肌梗死后护理的第一步，总体目标是减少心绞痛症状和改善结果。