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Precision Medicine for Dilated Cardiomyopathy in European and African Ancestry

欧洲和非洲血统扩张型心肌病的精准医学

基本信息

批准号：
9475697
负责人：
RAY E. HERSHBERGER
金额：
$ 220.64万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-27 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9475697
关键词：
Address Affect African Cardiomyopathies Cardiovascular system Categories Cessation of life Characteristics Classification Clinical Communication Consensus DNA Data Detection Diagnostic Dilated Cardiomyopathy Disease European Family Family history of Family member First Degree Relative Frequencies Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genetic Risk Genetic Screening Genetic screening method Genomics Genotype Goals Health Heart Heart Transplantation Heart failure Individual Intervention Lead Link Measures Medical Genetics Medicine Molecular Genetics Morbidity - disease rate Outcome Study Pathogenicity Patients Phase Phenotype Physicians Prevention Prevention strategy Primary idiopathic dilated cardiomyopathy Public Health Publishing Randomized Recommendation Recording of previous events Recurrence Risk Scourge Symptoms Test Result Testing Variant base care costs care outcomes clinical Diagnosis clinical research site cohort cost disability exome exome sequencing familial dilated cardiomyopathy follow-up gene discovery genetic information genetic linkage analysis genetic pedigree genome-wide genome-wide linkage impression improved inherited cardiomyopathy insight mortality non-genetic novel precision medicine prevent proband public health relevance racial difference rare variant recruit research clinical testing screening segregation standard of care tool tv watching uptake

项目摘要

DESCRIPTION (provided by applicant): Dilated cardiomyopathy of unknown cause (DCM), known clinically as idiopathic dilated cardiomyopathy, is the most common cardiomyopathy and is the leading cause of heart transplantation. By our estimates DCM affects approximately one million individuals, and so has a major impact on US public health. DCM is commonly asymptomatic until very late in its course when it causes heart failure, disability, and death. Because of its clinical course, any means to identify patients at risk for DCM or to detect DCM in its asymptomatic phase could provide enormous opportunity for intervention to extend lives and prevent late-stage disease. Within this paradigm precision medicine for DCM could greatly impact health care outcomes and costs. Recent advances in DCM genetics have introduced these possibilities, but unresolved questions of familial recurrence risk, genetic etiology, racial differences, and family-based screening must be addressed to move ahead. Our central hypothesis, based on our published studies, states that DCM has substantial genetic basis. For this study we hypothesize that: (a) 35% of probands of both European and African ancestry (EA/AA) will be classified as familial in a cohort recruited in a multicenter US consortium and given explicit recommendations and assistance to achieve the clinical screening of relatives; (b) approximately 40% of DCM probands, whether categorized as familial or non-familial, or as EA or AA, will have pathogenic or likely pathogenic variants in genes previously implicated in DCM; and (c) a tailored intervention to help DCM probands communicate DCM risk to their family members will improve the uptake and impact of necessary clinical and genetic testing. To test these hypotheses, we propose to: (1) estimate and compare the frequencies of EA and AA DCM probands classified as having familial DCM; (2) estimate and compare the proportions of probands with an identifiable genetic cause of DCM in groups defined by proband classification (familial/non-familial) and ancestry (EA/AA); and (3) evaluate the impact of a randomized intervention to aid and direct family communication on participation of at-risk family members in clinical screening and appropriate follow-up surveillance for DCM. These aims will be accomplished by recruiting a cohort of 1200 DCM probands (600 EA and 600 AA), performing cardiovascular clinical screening of 4800 family members, performing genetic testing of probands and affected family members by exome sequencing, returning genetic results, and randomizing probands to an intervention to improve family communication regarding DCM risk. Proving these hypotheses would be transformative for the field: rather than viewing DCM as only a clinical diagnosis, we would understand DCM as a genetic disease that should be managed using genetic diagnostic and family-based preventive strategies. Our study results would make precision medicine for DCM a reality.