An Integrated Genetic-Epigenetic Tool for the Prediction of CHD Incidence in African-Americans

ABSTRACTHeart disease is the leading cause of death in the United StatesCoronary heart diseaseCHDis the most common type of heart diseaseEvery yearmillions of Americans suffer otherwise preventable cardiac events resulting indeaths and $billion dollars of economic damage each yearThe prevalence of CHD varies by ethnicityNeverthelessfortunatelyCHD related morbidity and mortality can be prevented through the early identification of those at risk to undergo lifestyle modifications and medical treatmentHoweverthe current risk screening approaches are not sensitive across all ethnic groupsare expensive and require the aggregation of multiple testsUsuallyeven after these tests have been conductedadditional procedures such as an ECGstress test and coronary angiogram are required for CHD status ascertainmentThese steps are costly and more importantlyhinder timely decision making by physiciansThereforea more sensitive tool that is capable of ascertaining risk for CHD prior to an acute eventespecially one that captures ethnicity specific risk could lead to more effective prevention and treatment for all members of our societyUsing resources from the Framingham Heart StudyFHSwe have developed an integrated geneticepigenetic assessment tool that incorporates the effects of genetic variation on DNA methylationGxMeth effectsthat may overcome many of these shortcomings and be that NextGen Precision Medicine screening tool for CHDIn this Phase I applicationwe seek to test the generalizability and translation of our tool for CHD incidence prediction in an independently collected cohort of African American subjects characterized for CHDWe will take advantage of high performance computational techniques to understand whether our approach works in a non FHS populationSubsequentlyto demonstrate translational feasibility of predictive markerswe will couple our simple blood draw based approach and the droplet digital PCRddPCRtechnology to develop and validate methylation sensitive ddPCRMSddPCRassaysThis approach uses DNA from as little as a single drop of blooddoes not require extensive collection of clinical variables and will find widespread use as a quantitative biomarker for CHD in clinicalcivil and pharmaceutical drug development related applicationsUltimatelythe approaches proposed in this application will result in the introduction of a Precision Medicine tool encompassing an algorithm and a panel of MSddPCR assays based on a strong scientific premise for the prediction of CHD incidenceIt will also serve as a proof of concept project that will lead to a full scale Phase II examination to prospectively predict the onset of CHD in a large multi ethnic cohort as implemented in a set of easy to conduct MSddPCR assays that take advantage of the Bio Rad ddPCR platform that is in the process of gaining regulatory approval The purpose of this application is to demonstrate generalizability of a simple blood test that candetermine the likelihood of developing coronary heart disease in an African American cohortAsopposed to prior approachesthis NextGen test does not require extensive collection of clinicalvariablesand will be considerably more sensitive and specific than current measures