Genomic variants associated with angina and health status outcome after MI

点击翻译按钮获取中文摘要

 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.