Hypertension (HTN), a disease that affects over 65 million Americans, is one of the most common chronic diseases in the world. Hypertensive heart disease (HHD) phenotypes, including left ventricular (LV) hypertrophy (LVH), LV diastolic dysfunction (LVDD), LV systolic dysfunction (LVSD), and vascular hypertrophy are common and inter-related. Furthermore, HHD-endophenotypes are commonly worsened by co-morbid conditions such as diabetes, obesity, metabolic syndrome, and dyslipidemia, thus suggesting that common underlying pathologic processes control/modulate these phenotypes through gene-gene (GxG) and/or gene-environment (GxE) interactions. During the first 5 years of this project, the investigative team has identified genes involved in myocardial metabolism and inflammation as putative modulators of these highly complex HHD-related phenotypes. The overarching hypothesis of this study is that in HTN, metabolic-inflammatory gene pathways interact to develop HHD-endophenotypes. This hypothesis will be tested by conducting a phenotype-genotype clinical study in 1,650 unrelated Caucasians by performing a high-density genome-wide association (GWA) study where single nucleotide polymorphisms (SNPs) will be associated with quantitative HHD-endophenotypes. The existing DNA repository includes exquisite, quantitative cardiovascular, metabolic, environmental, and inflammatory phenotypes ideal for association studies of the genetic/molecular basis of HTN/HHD-endophenotypes. The hypothesis is supported by studies in animal models of HHD conducted by collaborators at our institution and others. We have assembled a multidisciplinary team with expertise in clinical/translational research, molecular cardiology, and statistical genetics/genetic epidemiology, and build upon an existing comprehensive repository of DNAs and arrays of exquisite clinical phenotypes in 1000 Caucasian subjects. The revised specific aims (SA) for this two-year project are SA1. Enhance existing study cohort of 1,000 subjects by recruiting and phenotyping an additional 300 subjects to achieve a study population of 1,300 Caucasians. SA2. Perform integrated GWA analysis to develop a global survey of SNPs in pathways relevant for the development of HHD-endophenotypes in the Caucasian cohort. Exploratory Specific Aim. Select 2 top-ranked interacting candidate genes, one from each network, for fine-mapping of HHD variants by deep resequencing. GWA data from the primary and validation studies will lead to the construction of an HHD-pathways resource database. This research will result in a clear understanding of HHD and will generate the first database of highly dense SNP genotypes augmented by pathway information for future studies of HTN/HHD-endophenotypes.
The reviewers of the original proposal identified multiple strengths of the proposal, including innovative approach, strong preliminary data, expertise and previous success of the applicant team, and significance of the proposal. They agreed that the proposed study addresses one of the biggest problems in cardiovascular disease with a reasonable chance of success., and recognized its unique strength and innovation in cutting-edge bio-informatics approach and characterization of endophenotypes. We would like to add that if funded, this two-year proposal would yield important new information related to HTN and HHD that would serve as the much-needed launching pad for subsequent R01 proposals by the PIs and Co-investigators within the next 12-18 mo. The renewal of this proposal would flow naturally from where this proposal ends, and would consist of the following general aims: 1. Continued increase in the study population to reach an estimated target of ~3,000 subjects;2. Continued work towards a refined annotation of selected SNPs by including functional characterization and network analysis to identify the most promising 25,000 SNPs for validation analysis;3. Validation of results using the Framingham Heart Study and HyperGEN databases to identify a set of top-ranked genes for deep resequencing of the HHD-endophenotype tails (i.e., 200 cases/200 controls) and perform integrated analysis using tools developed by the 2-year project. 4. As part of the programmatic goals of our group, we plan under a separate application, to continue to expand our recruitment, phenotyping, and genotyping efforts of African-Americans, a group that is particularly affected by the devastating effects of HTN and HHD. Finally, whereas the overarching goal of our research program is to elucidate the underlying mechanisms of HHD, future mechanistic proposals (using epigenomic techniques and animal models) will capitalize on the discoveries from this GWA study by identifying the functional gene variants and GxE interactions that increase or decrease HHD risk.
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