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.
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