The objective is to investigate whether the beta adrenergic receptor (BAR) genes: 1) are hypertension (HTN) genes, 2) are disease modifying genes in HTN; and/or 3) impact responsiveness to antihypertensive therapy. The long term objectives are to elucidate the role of the BAR in HTN and racial differences in HTN. They will test the hypotheses that the B1AR and/or B2AR genes: 1) are associated with HTN and racial differences in HTN; 2) influence the nocturnal blood pressure (BP) decline (dipper); and 3) are important determinants of the antihypertensive response to BAR-blocker therapy.
The specific aims i nclude:
Aim 1 a) Determine if the BAR genes are associated with HTN by comparing B1AR and B2AR genotypes, allele frequencies, and haplotypes between 200 hypertensives and 200 normotensives (equal numbers of blacks and whites).
Aim 1 b) Determine if the BAR genes are associated with racial differences in HTN by evaluating the association between the BAR genes and HTN independently among blacks and whites, and by comparing BAR genotypes/allele frequencies/haplotypes between hypertensive blacks and whites.
Aim 2) Determine the association between dipper status and BAR genes by comparing B1- and B2AR allele frequencies/genotypes/haplotypes in at least 25 nighttime BP dippers and 25 nondippers, as determined by ambulatory BP monitoring. Impact of BAR genes on racial differences in nondipper phenotype will be assessed by making the above comparisons with n greater than 25 in each racial group.
Aim 3) compare the antihypertensive response to metoprolol therapy in 40 patients selected for study based on their B1- and B2AR genotypes and haplotypes. Antihypertensive response will be assessed by 24 h ambulatory BP monitoring. The proposed studies are important because they aim to provide evidence about the role of the BAR genes in HTN and racial differences in HTN. If the B1- and/or B2AR genes are found to be HTN genes, specifically which contribute to racial differences in the disease, then persons with the """"""""HTN susceptible"""""""" BAR genotype might be identified early in life and targeted for aggressive preventive therapy. Such knowledge could also lead to improved therapeutic approaches, including gene therapy. Documentation that the BAR genes influence the nocturnal BP would be especially significant since it appears to be a major determinant of target organ damage with HTN, and may be an important cause of the racial differences in target organ damage. Better understanding of the mechanisms controlling nighttime BP could lead to improved therapeutic strategies and decreased target organ damage from HTN. Finally, discovery that the BAR genotype significantly impacts the BP response to B-blockers could lead to improved patient outcomes, as patients could be genotyped prior to institution of B-blocker therapy, thus avoiding this therapy in those likely to respond
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