Essential hypertension, like all complex diseases, is characterized by multifaceted interactions between genetic and environmental factors. Among environmental variables, dietary salt intake has long been recognized as a major modulator of blood pressure in some (sodium- sensitive) but not other (sodium-resistant) individuals. This spread of responses to an environmental influence is typical for ecogenetic interactions, where the phenotype effects of a given external perturbation differs according to the specific genetic make-up of the individual. Clinically, sodium-sensitivity plays an important role in the incidence of the disease as well as in the management of hypertensive patients, particularly among African-Americans. The study of sodium- dependent hypertensive mechanisms is therefore the focal point of the present SCOR application. The project at hand proposes to use a rat model of sodium-sensitive hypertension to identify and characterize genes that confer sodium-responsive modulation of blood pressure. We have previously crudely mapped two genes, BP-SP1 on chr. 10, and BP/DNa-1 on chromosome 6, that are involved in sodium-sensitivity in the spontaneously hypertensive, stroke prone rat. Using congenic experiments we have found that BP/SP-1 consists of two independent, but interacting loci, of which one, BP/SP-1b appears to be primarily involved in conferring sodium sensitivity.
The specific aims of the presently proposed study are: (i) Development of a panel of targeted markers in the region of BP/SP- 1b and BP/DNa-1; (ii) Breeding of congenic lines carrying BP/SP-1b and BP/DNa-1, respectively, on WKY background. (iii) Precision phenotyping of these strains will allow pinpoint localization of the two genes and characterization of their specific phenotypic characteristics. (iv) Identification and characterization of the two genes will be pursued by positional cloning approaches.
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