Increased arterial blood pressure [BP] in the absence of known causes, essential hypertension [EHYT], is a significant risk factor for coronary heart disease, cerebrovascular disease and renal disease, and reaches epidemic proportions in both non-Hispanic Whites and African-Americans in the United States. In the previous cycle of this research, we evaluated the influence of variation in established candidate genes on variation in BP levels in the population at large and carried out the first genome wide linkage analysis to identify new BP candidate genes (i.e. positional candidate genes). In this proposed cycle of research, we will use DNA sequencing to identify variation in the coding and regulatory regions of newly identified positional candidate genes, and carry out association analyses between this DNA sequence variation and BP levels and EHYT status.
In Aim 1, we will use high through-put DNA sequencing in 24 non-Hispanic Whites and 24 African-Americans to identify DNA sequence variation in the coding and 5' regulatory regions of each positional candidate gene. To accomplish Aim 2, we will type the variable sites identified in Aim 1 in a sample of 573 randomly ascertained three-generation pedigrees containing 3,938 individuals from Rochester, MN, and 515 hypertension cases and 471 normotensive controls from Jackson, MS. We will then use graphical and statistical methods, including transmission disequilibrium tests [TDTs] and regression tree methods, to evaluate the relationship between the DNA sequence variation and the distribution of systolic and diastolic BP and EHYT status. We will also determine whether the influence of the genetic variation is homogeneous among strata defined by gender, age, body size, smoking status and population. The studies proposed here will move us one step closer to defining functional allelic variation influencing interindividual variation in BP levels and the risk of developing EHYT in the population-at-large.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL051021-10
Application #
6638357
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Sholinsky, Phyliss
Project Start
1994-07-08
Project End
2004-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
10
Fiscal Year
2003
Total Cost
$1,020,681
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Genetics
Type
Schools of Public Health
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Non, Amy L; Gravlee, Clarence C; Mulligan, Connie J (2012) Education, genetic ancestry, and blood pressure in African Americans and Whites. Am J Public Health 102:1559-65
International Consortium for Blood Pressure Genome-Wide Association Studies (see original citation for additional authors) (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103-9
Johnson, Andrew D; Newton-Cheh, Christopher; Chasman, Daniel I et al. (2011) Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. Hypertension 57:903-10
Won, Joong-Ho; Ehret, Georg; Chakravarti, Aravinda et al. (2011) SNPs and other features as they predispose to complex disease: genome-wide predictive analysis of a quantitative phenotype for hypertension. PLoS One 6:e27891
Fox, Ervin R; Klos, Kathy L; Penman, Alan D et al. (2010) Heritability and genetic linkage of left ventricular mass, systolic and diastolic function in hypertensive African Americans (From the GENOA Study). Am J Hypertens 23:870-5
Rodin, Andrei S; Litvinenko, Anatoliy; Klos, Kathy et al. (2009) Use of wrapper algorithms coupled with a random forests classifier for variable selection in large-scale genomic association studies. J Comput Biol 16:1705-18
Turner, Stephen T; Fornage, Myriam; Jack Jr, Clifford R et al. (2009) Genomic susceptibility Loci for brain atrophy, ventricular volume, and leukoaraiosis in hypertensive sibships. Arch Neurol 66:847-57
Dmitrieva, Renata I; Hinojos, Cruz A; Grove, Megan L et al. (2009) Genome-wide identification of allelic expression in hypertensive rats. Circ Cardiovasc Genet 2:106-15
Montasser, May E; Shimmin, Lawrence C; Hanis, Craig L et al. (2009) Gene by smoking interaction in hypertension: identification of a major quantitative trait locus on chromosome 15q for systolic blood pressure in Mexican-Americans. J Hypertens 27:491-501
Sun, Yan V; Jacobsen, Douglas M; Turner, Stephen T et al. (2009) A Fast Implementation of a Scan Statistic for Identifying Chromosomal Patterns of Genome Wide Association Studies. Comput Stat Data Anal 53:1794-1801

Showing the most recent 10 out of 43 publications