Familial Dilated Cardiomyopathy: Detection/Gene Mapping

描述(申请人提供)：心力衰竭通常由扩张型心肌病(DCM)引起，一种常见的形式是特发性扩张型心肌病(IDC)。现在有大量证据表明，多达一半的IDC患者的家庭成员受到类似的影响，有两个或两个以上受影响的家庭被指定为家族性扩张型心肌病(FDC)。&gt；20基因的突变与FDC有关，支持其遗传学基础。尽管取得了这一进展，我们估计已经确定了30%的FDC的遗传原因，而且几乎所有的遗传原因都发生在高加索人身上，尽管黑人有更多的DCM。俄勒冈健康与科学大学(OHSU)于1993年建立了一项FDC研究计划，以确定FDC的遗传基础。我们对FDC的300个家系进行了评估，其中包括5个适合进行连锁分析的非常大的家系；其中一个是非常大的非裔美国人家庭。我们在与几个感兴趣的地区进行联系分析方面取得了实质性进展。所有的临床和家系数据都被放入了为家庭研究而设计的关系型数据库程序Progeny中，大大提高了我们的效率。2007年年中，该研究项目迁至佛罗里达州迈阿密的迈阿密大学米勒医学院/杰克逊纪念医院综合体，为研究提供了极大的丰富的黑人和拉美裔人口。该计划还与新的迈阿密人类基因组学研究所(MIHG)合作，提供了大大加强的合作、实验方法和研究基础设施。对于这次更新，我们建议(1)重新筛选我们的五个大连锁家系，最初在1995-2000年间进行筛查，以确定新的受影响的家庭成员。我们提供了令人信服的数据，表明新感染的受试者很可能被识别出来，从而加强了连锁分析的统计能力，并加强了我们对致病FDC疾病基因的搜索。我们还将继续识别新的FDC血统，无论大小，我们招募少数族裔家庭，特别是黑人家庭的努力，应该在南佛罗里达州非常成功。我们还将(2)在21个已知DCM疾病基因的突变通过测序排除后，在我们的连锁家系中定位与FDC有关的基因。MIHG将协助对5个连锁家系进行全基因组SNP基因分型，并对结果进行连锁分析。基因作图研究将缩小感兴趣的区域，定向候选基因研究将用于识别新的FDC疾病基因。公共卫生相关性：扩张型心肌病在很大程度上是一种遗传性心肌疾病，但只有一小部分遗传原因已被确定。我们的目标是识别更多的疾病基因，这将有助于更好地理解人类心力衰竭的原因。

DESCRIPTION (provided by applicant): Heart failure usually results from dilated cardiomyopathy (DCM), and one common form is idiopathic dilated cardiomyopathy (IDC). Considerable evidence now indicates that up to one-half of patients with IDC have similarly affected family members, and families with two or more affected are designated as having familial dilated cardiomyopathy (FDC). Mutations in >20 genes have been associated with FDC, supporting its genetic basis. Despite this progress, we estimate < 30% of the genetic causation of FDC has been identified, and almost all in Caucasians even though blacks have more DCM. An FDC research program was established in 1993 at the Oregon Health & Sciences University (OHSU) to determine the genetic basis of FDC. We have evaluated >300 families for FDC, including five very large pedigrees suitable for linkage analysis; one is a very large African-American family. We have made substantial progress with linkage analysis with several regions of interest. All clinical and pedigree data have been placed into Progeny, a relational database program designed for family studies, greatly improving our efficiency. In mid 2007 this research program relocated to the University of Miami Miller School of Medicine/Jackson Memorial Hospital complex in Miami, FL providing a dramatically enriched population of blacks and Hispanics for study. This program is also associated with the new Miami Institute for Human Genomics (MIHG), providing greatly strengthened collaboration, experimental methods and research infrastructure. For this renewal we propose to (1) rescreen our five large linkage pedigrees, initially screened 1995-2000, to identify newly affected family members. We provide compelling data suggesting that that newly affected subjects are likely to be identified, thereby strengthening the statistical power at linkage analysis and enhancing our search for causative FDC disease genes. We will also continue to identify new FDC pedigrees of any size, and our efforts to recruit families of minorities, particularly blacks, should be highly successful in south FL. We will also (2) map the genes responsible for FDC in our linkage pedigrees after mutations in 21 known DCM disease genes have been excluded by sequencing. The MIHG will assist with genome-wide SNP genotyping for the 5 linkage pedigrees, and results analyzed by linkage analysis. Gene mapping studies will narrow regions of interest, and directed candidate gene studies will be used to identify novel FDC disease genes. PUBLIC HEALTH RELEVANCE: Dilated cardiomyopathy is largely a genetic disease of the heart muscle, but only a small fraction of genetic cause has been identified. We aim to identify more of the disease genes, which will lead to greater understanding of the causes of human heart failure.