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.

Public Health Relevance

Hypertension is a condition that affects ~25-35% of the adult population in the United States, and is associated with high complication rate and high mortality. The purpose of this research is to identify genes that may be implicated in hypertension and its associated complications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071782-06
Application #
7851398
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Liang, Isabella Y
Project Start
2002-12-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$937,040
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Yang, Wei; Charles Gu, C (2014) Random forest fishing: a novel approach to identifying organic group of risk factors in genome-wide association studies. Eur J Hum Genet 22:254-9
Yang, Wei; Gu, C Charles (2013) A whole-genome simulator capable of modeling high-order epistasis for complex disease. Genet Epidemiol 37:686-94
de las Fuentes, Lisa; Yang, Wei; Dávila-Román, Victor G et al. (2012) Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets. Eur J Hum Genet 20:1168-73
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Yang, Wei; de las Fuentes, Lisa; Dávila-Román, Victor G et al. (2011) Variable set enrichment analysis in genome-wide association studies. Eur J Hum Genet 19:893-900
Juang, Jyh-Ming Jimmy; de Las Fuentes, Lisa; Waggoner, Alan D et al. (2010) Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function. BMC Med Genet 11:65
Subherwal, Sumeet; de las Fuentes, Lisa; Waggoner, Alan D et al. (2010) Central aortic pressure is independently associated with diastolic function. Am Heart J 159:1081-8
de Las Fuentes, Lisa; Spence, Karen E; Dávila-Román, Victor G et al. (2010) Are normative values for LV geometry and mass based on fundamental imaging valid with use of harmonic imaging? J Am Soc Echocardiogr 23:1317-22

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