HYPERGEN: GENETICS OF LEFT VENTRICULAR HYPERTROPHY

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DESCRIPTION: (Adapted from the Investigator's Abstract) Left ventricular (LV) hypertrophy is a common condition that profoundly affects morbidity and mortality from cardiovascular diseases. The long-term objective of this study, the HyperGEN (Genetics of LV Hypertrophy) study is to identify genetic predictors influencing susceptibility to LV hypertrophy and cardiac dysfunction. During the initial project period, echocardiography was performed on 3,000 black and white participants in the parent HyperGEN study, a multicenter study designed to determine the genetics of hypertension. As a result, most study participants were family members ascertained on hypertension. The investigators carried out genome-wide linkage analyses, and identified chromosomal regions with a high probability of harboring genetic loci contributing the interindividual variation in LV and myocardial contractility. In this renewal application, the investigators propose to extend this work with three complementary specific aims to further understanding of the genetics of echocardiography phenotypes. Specific Aim 1 proposes to further characterize genomic regions contributing to interindividual variation in LV mass and related cardiographic phenotypes among 1,900 hypertensive sibs, 400 of their normotensive offspring, and an additional 720 offspring to be recruited by the parent HyperGEN study beginning in Summer, 2000. To enhance statistical power to detect genetic linkage and association for narrowing genomic regions, the investigators will conduct echocardiography on 480 of these offspring who are not being phenotyped by HyperGEN. Specific Aim 2 will consist of identifying positional candidate genes within the implicated genomic regions based on their known function and chromosomal location. To facilitate this aim, the investigators will use results from rat models to identify regions of homology in humans with know gene locations in the rat. Specific Aim 3 will investigate whether genes contributing to LV mass in hypertensives also contribute to the phenotype in normotensives, and thereby characterize the full spectrum of LV mass and related cardiac phenotypes. This will require using the randomly ascertained sample from the HyperGEN study to recruit and examine sibling and offspring of normotensive individuals who have LV mass in the upper 75th percentile of the LV mass distribution. The investigators will examine allelic variation in the candidate genes identified in specific Aim 2 in this normotensive sample ascertained on increased LV mass. Finally, the investigators will replicate these findings in a second population-based sample of normotensive with LV hypertrophy and their age and sex matched controls. Overall, the study represents a complementary approach, from animal to human, to further understanding of the genetic architecture of LV hypertrophy.