Pathologic left ventricular hypertrophy (LVH) is a major determinant of morbidity and mortality for patients with cardiovascular disease. The molecular mechanisms responsible for the development of LVH have not been well characterized. Alterations in myocardial energy metabolism are implicated in the pathogenesis of contractile dysfunction and heart failure in both animals and humans. Peroxisome proliferator-activated receptor-alpha (PPAR-(alpha), a transcriptional regulator of myocardial fatty acid (FA) transport and beta-oxidation enzymes, is down-regulated in pathologic LVH in association with decreased myocardial FA metabolism and increased glucose utilization. Variants of the human PPAR-alpha gene likely modulate phenotypic expression of LVH and ventricular function in humans. We hypothesize that individuals with single nucleotide variations of the PPAR-alpha-gene that render this transcriptional regulator less active will display greater degrees of LVH and alterations in myocardial fatty acid metabolism. The hypothesis will be tested by the following specific aims: 1) Characterization of eight single nucleotide variations in the human PPAR-alpha gene that correlate with the presence and severity of LVH, and 2) Characterization of the phenotypic expression of G/C intron 7 polymorphism in the human PPAR-alpha gene in terms of myocardial fatty acid metabolism. As previously show in animal models of pressure-overload hypertrophy and in heart failure, we have recently demonstrated similar abnormalities in myocardial metabolism, contractile function and efficiency in patients with LVH. We have built upon our strengths in cardiac imaging and have assembled a multidisciplinary team with expertise in molecular mechanisms regulating the cardiac hypertrophic program, molecular genetics and genetic epidemiology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071782-02
Application #
6784614
Study Section
Special Emphasis Panel (ZRG1-DMG (01))
Program Officer
Buxton, Denis B
Project Start
2003-07-29
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$711,074
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
Barve, Ruteja A; Gu, C Charles; Yang, Wei et al. (2016) Genetic association of left ventricular mass assessed by M-mode and two-dimensional echocardiography. J Hypertens 34:88-96
Climer, Sharlee; Yang, Wei; de las Fuentes, Lisa et al. (2014) A custom correlation coefficient (CCC) approach for fast identification of multi-SNP association patterns in genome-wide SNPs data. Genet Epidemiol 38:610-21
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
Kraja, Aldi T; Lawson, Heather A; Arnett, Donna K et al. (2012) Obesity-insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice. Metabolism 61:1129-41
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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