The objective is to identify modifier genes that affect hypertrophy in human familial hypertrophic cardiomyopathy (FHCM) and determine whether pharmacological inhibition of their effects can induce regression of established hypertrophy in a transgenic rabbit model of human FHCM. FHCM, an autosomal dominant disorder occurring 1 in 500, is the most common cause of sudden cardiac death (SCD) in the young. In the elderly, occurring 9 in 500, it is a major cause of mortality and morbidity. Ten genes and >100 mutations were identified with the majority due to 3 genes. Reasons to search selectively for modifier genes of hypertrophy are: hypertrophy is the main determinant of mortality and morbidity in FHCM; it is required for the diagnosis; it is an independent risk factor for SCD and failure due to FHCM and other causes; can be quantified non-invasively and hypertrophy whether due to FHCM or other causes, is known to be modified genetically. Hypertrophy due to any cause is always associated with fibrosis, a putative substrate for SCD. Genotype-phenotype correlation studies indicate marked variation in age of onset and severity of hypertrophy even within the same family with the same mutation. The variation is due in large part to modifier genes and is suggested by association studies (e.g. ACE gene) but a systematic genomic search is necessary. This requires a repository of families with FHCM, a mathematical model and ideally an established genetic animal model of FHCM to confirm the predicted biological effect of modifier genes. Recent application of the Monte Carlo Markov Chain Methods (MCMC) in multiple families with Alzheimer's was shown to be highly sensitive in detecting modifier genes. Thus, utilizing 50 previously well-characterized families with FHCM from a computerized database, the genome will be screened initially with 400 DNA markers and analyzed by the MCMC methods to identify regions with modifier genes (Aim 1) followed by additional closely spaced markers in these regions to identify candidate genes (Aim 2). Independently, 350 unrelated probands with FHCM will be analyzed to determine if an association exists between hypertrophy and SNPS identified in candidate modifier genes (Aim 3). An established rabbit model with a phenotype identical to human FHCM will be utilized to determine the biological effect of identified candidate modifier genes. The ACE gene, previously implicated as a modifier of hypertrophy, is the initial candidate. It's effect will be inhibited with Losartan, a renin- angiotensin system (RAS) blocker, in the rabbit model to determine if there is regression of hypertrophy. Similarly, as other modifiers are identified they will be tested in the rabbit model. Identification of modifiers is necessary to assess prognosis and develop more comprehensive treatment. Treatment found to induce regression of hypertrophy in the rabbit with FHCM will most likely also induce regression of hypertrophy in human FHCM and hypertrophy due to other cardiac causes.
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