The purpose of this proposal is to investigate the genetic basis of essential hypertension in African American men and women. Hypertension in Blacks is often associated with salt sensitivity, a condition which appears to be genetically determined. This """"""""intermediate phenotype"""""""" of essential hypertension is at least in part mediated by renal adrenergic receptors, which are also genetically regulated. We hypothesize that genetic variability in these receptors leads to salt sensitivity, and thus to the pathogenesis of hypertension in Blacks. We will address this hypothesis by robust sib-pair analysis, with the adrenergic receptors that regulate renal sodium excretion and renal vascular tone as the candidate genes. A total of 300 Black sib-pairs will be phenotyped with respect to sodium sensitivity, using a standardized saline-loading/volume-depletion protocol. Genomic DNA will be extracted from leukocytes of all sibs and their parents. DNA will be screened for variants of the genes encoding the alpha1-, alpha2c2-, alpha2c4-, alpha2c10-, beta1-, and beta2-adrenergic receptors. initially we will test RFLPs that have been described in the adrenergic receptor genes of normal Caucasians. If these markers are sufficiently informative in African Americans, the region flanking the restriction enzyme site(s) will be sequenced, and a PCR-based rapid screening method will be developed to detect sequence variations in the sample population. If one or more candidate adrenergic receptor gene is not sufficiently polymorphic by RFLP analysis, we will screen for sequence variation by denaturing gradient gel electrophoresis and other methods, including direct sequencing, as necessary. Linkage between salt sensitivity and sequence variations will be tested by the robust sib-pair methods of Haseman and Elston. Linkage relationships suggested by robust sib-pair methods will be confirmed using LOD score analysis.
| Svetkey, L P; Chen, Y T; McKeown, S P et al. (1997) Preliminary evidence of linkage of salt sensitivity in black Americans at the beta 2-adrenergic receptor locus. Hypertension 29:918-22 |
| Svetkey, L P; George, L K; Tyroler, H A et al. (1996) Effects of gender and ethnic group on blood pressure control in the elderly. Am J Hypertens 9:529-35 |
| Svetkey, L P; McKeown, S P; Wilson, A F (1996) Heritability of salt sensitivity in black Americans. Hypertension 28:854-8 |
| Svetkey, L P; Timmons, P Z; Emovon, O et al. (1996) Association of hypertension with beta2- and alpha2c10-adrenergic receptor genotype. Hypertension 27:1210-5 |
