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

• 批准号: 9284542
• 负责人: RAY E. HERSHBERGER
• 金额: $ 276.82万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9284542
• 关键词: Address; Affect; African; Cardiomyopathies; Cardiovascular system; Categories; Cessation of life; Characteristics; Classification; Clinical; Communication; Congenital cardiomyopathy; Consensus; Data; Detection; Diagnostic; Dilated Cardiomyopathy; Disease; European; Family; Family history of; Family member; First Degree Relative; Frequencies; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Screening; Genetic screening method; Genomics; Genotype; Goals; Health; Healthcare; Heart; Heart Transplantation; Heart failure; Hereditary Disease; Individual; Intervention; Lead; Link; Measures; Medical Genetics; Medicine; Molecular Genetics; Morbidity - disease rate; Outcome; Outcome Study; Pathogenicity; Patients; Phase; Phenotype; Physicians; Prevention; Prevention strategy; Primary idiopathic dilated cardiomyopathy; Public Health; Publishing; Randomized; Recommendation; Recording of previous events; Recruitment Activity; Recurrence; Risk; Scourge; Symptoms; Test Result; Testing; Variant; base; 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; insight; mortality; non-genetic; novel; precision medicine; prevent; proband; public health relevance; racial difference; rare variant; research clinical testing; screening; segregation; standard of care; tool; tv watching; uptake

 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.

 描述（由适用提供）：未知原因的扩张心肌病（DCM），在临床上被称为特发性扩张性心肌病，是最常见的心肌病，是心脏移植的主要原因。根据我们的估计，DCM影响了大约一百万个人，因此对美国的公共卫生产生了重大影响。 DCM通常是不对称的，直到其导致心力衰竭，残疾和死亡的过程中很晚。由于其临床过程，任何鉴定有DCM风险或在其不对称阶段检测DCM患者的手段都可以为延长生命和预防晚期疾病的巨大机会提供巨大的机会。在此范式中，DCM的精确医学可能会极大地影响医疗保健结果和成本。 DCM遗传学的最新进展引入了这些可能性，但尚未解决家庭复发风险，通用病因，种族的问题 差异和基于家庭的筛查必须进行前进。基于我们发表的研究，我们的中心假设指出，DCM具有大量的遗传基础。在这项研究中，我们假设：（a）欧洲和非洲血统（EA/AA）的35％的问题将被归类为在美国多中心联盟中招募的同伙中，并提供明确的建议和帮助，以实现亲戚的临床筛查； （b）大约40％的DCM问题，无论是归类为家庭还是非家庭或EA或AA，都将在先前在DCM中实施的基因中具有致病性或可能的致病性变异； （c）量身定制的干预措施来帮助DCM问题将DCM风险传达给其家人，将改善必要的临床和基因检测的吸收和影响。为了检验这些假设，我们建议：（1）估计和比较EA和AA DCM问题的频率，分类为家庭DCM； （2）估算和比较问题的比例与由概率分类（家族/非家庭）和祖先（EA/AA）定义的组中DCM的可识别遗传原因（EA/AA）； （3）评估随机干预对辅助和直接家庭沟通对处于危险家庭成员参与临床筛查的参与以及DCM适当的随访监视的影响。这些目标将通过招募1200个DCM检验（600 EA和600 AA），对4800个家庭成员进行心血管临床筛查，进行基因测试，并通过Eximome测序对家庭成员进行遗传测试，并通过返回的遗传结果进行遗传结果，并随机对家庭进行干预的沟通，从而对家庭进行了差异。证明这些假设对该领域具有变革性：而不是将DCM视为临床诊断，我们会将DCM理解为一种遗传疾病，应使用遗传诊断和基于家庭的预防策略进行管理。我们的研究结果将使DCM成为现实。