We and others have shown that cardiovascular reactivity (CVR) to acute laboratory stress is a stable and heritable trait and predictive of future blood pressure (BP) levels and essential hypertension (EH). The sympathetic nervous system (SNS) has a major role in BP regulation and adrenergic receptor subtypes mediate BP responses to acute challenges. As such, our hypothesis is that individual differences in CVR are partly determined by variation in genes encoding for adrenergic receptors mediating the sympathoadrenal response to stress. There is increasing evidence that this cardiovascular response is regulated by multiple adrenoceptor subtypes with structural homology. To date, nine homologous adrenergic receptor subtypes have been described. Only one study has found a gene-gene interaction upon CV disease incorporating two adrenergic receptor subtypes. Genetic variants in all the nine adrenergic receptor subtypes have never been investigated in a single study. This R-21 application proposes to evaluate the effects of genetic variants in all of the nine adrenergic receptor subtype genes, alone or in combination, on CVR and other quantitative cardiovascular traits in a population of 1048 healthy youth. Subjects are Black and White twins that have already been comprehensively phenotyped as part of the Georgia Cardiovascular Twin Study (HL56622). Racial differences in adrenoceptor gene effects will receive special attention, because such differences may offer a partial explanation for the higher prevalence of EH in Blacks. Primary measures are systolic BP at rest and in response to two behavioral stressors. Secondary measures are diastolic BP, cardiac output and total peripheral resistance (TPR) at rest and in response to the stressors, left ventricular mass (LVM), endothelium dependent arterial dilation to reactive hyperemia (EDAD), arterial stiffness and 24-hour ambulatory BP. We propose to expand this data set through collection of buccal cell DNA from the parents of the twins, enabling us to perform (i) TDTs (transmission disequilibrium tests) and (ii) haplotype reconstruction and analyses. This candidate gene study in a large group of Black and White twins including TDT and haplotype analyses provides an innovative approach to help identify individuals at particular risk for the development of EH and improve options for primary prevention as well as individualized therapy of EH (pharmacogenetics). ? ?
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