Genomic variants associated with angina and health status outcome after MI

 描述（由申请人提供）： 很少有人关注以患者为中心的健康状况结局，如心绞痛、抑郁和心肌梗死（MI）后生活质量下降，但这些往往是患者最关心的因素。在美国有超过1000万人患有心绞痛，并且每年发生大约500，000个新病例，估计每年花费200亿美元。我们建议通过使用TRIUMPH人群和NIH资助的队列，在入院时、MI后1个月、6个月和1年进行精确的疾病特异性健康状态评估，沿着裁定的1年主要不良心血管事件和5年死亡率，确定导致MI后心绞痛和健康状态结局个体间差异的新型基因组和非基因组因素。该研究小组特别有资格进行这项研究，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具有专长。总的来说，我们将致力于实现以下目标：目标1。心肌梗死后心绞痛个体间变异的新基因组和非基因组因素的鉴定和验证本AIM将分为两个阶段进行。第一个是继续以集中和顺序的方式全面识别导致MI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SMART扫描，生长曲线估计，多效性和崩溃的方法来实现这一目标。该目标的第二阶段是验证我们在初始资助周期中确定的基因组预测因子，并继续验证所有新确定的基因组变体。我们打算使用多个验证队列来验证和扩展我们的研究结果，包括INFORM、PREMIER、巴里2D和GENESIS-PRAXY研究。AIM 2.旨在减少心肌梗死后心绞痛的基因型引导的心肌梗死后治疗的初步研究我们建议使用CHRNA5 rs16969968变体作为我们的初步病例，并使用一种新的预后建模工具（PRISMTM），该工具允许使用患者特异性数据运行多变量模型来预测心肌梗死后结局，以显示将基因型引导的治疗纳入心肌梗死后治疗的可行性。这项初步研究将为个性化、基因型指导的心肌梗死后治疗奠定基础，旨在减少心肌梗死后患者的心绞痛症状和改善生活质量。这些目标的成功执行将使我们能够帮助实施NINR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策略，改善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MI后心绞痛相关的基因组和非基因组因素，并启动个性化MI后护理的第一步，其总体目标是减少心绞痛症状和改善结局。

 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.