PEDIGREE ANALYSIS OF HYPERTENSION MARKERS

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Essential hypertension is a multifactorial disease of unknown etiology that contributes significantly to cardiovascular death and disability. Identification and characterization of genes that affect an individual's risk of developing hypertension could allow for early intervention and, perhaps, prevention or cure. Genetic analyses of family data on hypertension, however, have been uninformative or contradictory, probably because of the multifactorial nature of this disease. Using a combination of statistical and molecular genetic approaches, we propose to identify and characterize major genes that affect five biochemical markers of hypertension (atrial natriuretic peptide levels, three markers of erythrocyte sodium transport, and urinary kallikrein levels), using data obtained on a population of more than 900 pedigreed baboons. The baboon is well-established animal model for the study of genetic factors affecting cardiovascular disease. We first will perform segregation analyses to identify major genes that affect the five intermediate phenotypes. To locate and characterize the (potential) major genes, we will perform linkage and measured genotype analyses, using data on molecular genetic markers. We will develop DNA markers for five candidate loci and type 900 pedigreed baboons to meet this latter objective. Genotypic data on an additional 39 biochemical and molecular markers also will be available for use in the linkage and measured genotype analyses. Finally, as these five intermediate phenotypes are associated with different blood pressure regulatory systems, we will use multivariate genetic analysis methods to test for interaction among the (potential) major genes affecting blood pressure. Theses results may provide essential information in regard to the basic cellular mechanisms involved in the genetic control of blood pressure regulation. Several researchers also have found evidence of interactions between risk factors of hypertension and atherosclerosis. We already have identified major genes in our baboon population for several lipoprotein phenotypes that are risk factors for atherosclerosis. Thus, we have a unique opportunity to estimate the effects of interactions between genetic factors for both hypertension and atherosclerosis that may contribute to risk of cardiovascular disease. These genetic analyses should be especially powerful because the effects of confounding environmental factors, such as diet, have been minimized in our pedigreed baboon colony.