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.
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.
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