Precision Medicine for Dilated Cardiomyopathy in European and African Ancestry

 说明(申请人提供)：原因不明的扩张型心肌病(DCM)，临床上称为特发性扩张型心肌病，是最常见的心肌病，也是心脏移植的主要原因。据我们估计，DCM影响了大约100万人，因此对美国公共卫生产生了重大影响。扩张型心肌病通常是无症状的，直到病程很晚的时候才会导致心力衰竭、残疾和死亡。由于其临床过程，任何识别扩张型心肌病风险的方法或在无症状阶段检测扩张型心肌病的方法都可以为干预延长生命和预防晚期疾病提供巨大的机会。在这种模式下，DCM的精准医学可以极大地影响卫生保健结果和成本。DCM遗传学的最新进展引入了这些可能性，但尚未解决的问题包括家族复发风险、遗传病因学、种族 为了取得进展，必须解决以家庭为基础的筛查问题。我们的中心假设，基于我们已发表的研究，表明DCM有实质性的遗传基础。对于这项研究，我们假设：(A)在一个多中心的美国财团招募的队列中，35%的欧洲和非洲血统先证者(EA/AA)将被归类为家族性DCM先证者，并给予明确的建议和帮助，以实现亲属的临床筛查；(B)大约40%的DCM先证者，无论是家族性的还是非家族性的，或者作为EA或AA，将在先前涉及DCM的基因中具有致病或可能的致病变异；以及(C)帮助DCM先证者向其家庭成员传达DCM风险的量身定制的干预措施将提高必要的临床和基因检测的接受度和影响。为了验证这些假设，我们建议：(1)估计和比较被归类为家族性DCM的EA和AA DCM先证者的频率；(2)估计和比较先证者分类(家族性/非家族性)和祖先(EA/AA)定义的组中具有DCM可识别遗传原因的先证者的比例；以及(3)评估随机干预对高危家庭成员参与DCM临床筛查和适当的后续监测的影响。这些目标将通过招募1200名DCM先证者(600名EA和600名AA)，对4800名家庭成员进行心血管临床筛查，通过外显子组测序对先证者和受影响的家庭成员进行基因测试，返回遗传结果，并将先证者随机分配到干预措施中来实现，以改善关于DCM风险的家庭沟通。证明这些假设将对该领域产生革命性的影响：我们将把扩张型心肌病理解为一种遗传性疾病，应该使用遗传诊断和基于家庭的预防策略来管理，而不是仅仅将其视为一种临床诊断。我们的研究成果将使扩张型心肌病的精准医学成为现实。

 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.