Sodium Transport: Genetics and Hypertension

BACKGROUND: Blood pressure has a continuous unimodal distribution in the general population. Individuals with levels elevated above the 80th percentile suffer from hypertension, a major cause of cardiovascular morbidity and mortality. Over 95 percent of hypertensives have no other primary disease and are said to have essential hypertension. Pedigree and twin studies indicate that genetic differences account for a large fraction of the interindividual variation in blood pressure. In 1984 when the study began, no genetic loci had yet been identified that were useful markers for essential hypertension or served as probes into the biological basis for interindividual blood pressure variability. Environmental factors also influence blood pressure; increased dietary intake of sodium chloride, in particular, elevates blood pressure and may contribute to the development of essential hypertension in some people. It was hypothesized that genetically determined alterations in the metabolism of sodium ion occur in a subset of the population that is at increased liability to develop elevated blood pressure upon exposure to the usual range of dietary sodium intake Reports of altered sodium transport in the red blood cells of individuals with essential hypertension and their offspring stimulated interest in this hypothesis. Several proposals were offered to explain how alterations in sodium transport similar to those observed in red blood cells could lead to elevated blood pressure when present in the renal tubules or vascular smooth muscle. Studies of the sodium-lithium countertransport system indicated that red blood cell sodium transport pathways may provide informative phenotypes that relate blood pressure and essential hypertension more closely with genetic factors. Numerous laboratories have confirmed that the maximal rate of sodium-lithium countertransport is increased in red blood cells from individuals with essential hypertension. The sodium-lithium countertransport is normal in secondary forms of hypertension and increased levels in essential hypertension cannot be attributed to age, body size, gender or dietary salt intake. The highest levels are observed in individuals with a positive family history of essential hypertension and the lowest levels occur in normotensive controls without hypertensive relatives. DESIGN NARRATIVE: When the study began in 1984, the objective was to determine whether genetic alterations in pathways of sodium transport in the red blood cells of children could predict their risk of developing primary hypertension in adulthood. Approximately 600 children between 7 and 18 years of age were randomly selected as index cases for family studies. Each participating member of the pedigrees studied underwent venipuncture for withdrawal of whole blood. A medical history was obtained from each family member visiting the clinic and a physical examination was conducted. Existing medical records for all living and deceased adult relatives in the 600 pedigrees were reviewed. In addition, 40 normotensive adult members of 300 pedigrees underwent metabolic balance and renal clearance studies, as well as ambulatory blood pressure recordings. Segregation analysis of pedigree data was carried out to determine the most likely mode for genetic transmission of the sodium-lithium counter-transport phenotype. Baseline genetic information about sodium-lithium was related to the prevalence of primary hypertension in the families of index children. Additional phenotypes involved in blood pressure regulation were also studied including renal proximal tubular sodium reabsorption, atrial natriuretic peptide, sodium-potassium adenosinetriphosphate pump, and sodium-potassium cotransport. The study was renewed several times, the last in 1992 to continue work on the genetic basis of interindividual variation in risk of essential hypertension in the population at large using the Rochester Family Heart Study (RFHS). The RFHS was used to address three major questions: 1) Which intermediate biochemical, physiological, and anthropomorphic traits predicted blood pressure and contributed to the pathogenesis of essential hypertension 2) Did allelic variation in one or more genes have large effects on any of these intermediate traits? 3) Did information about allelic variation improve prediction of risk of essential hypertension beyond what was provided by measure of the intermediate traits? The study completion date listed in this record was obtained from the "End Date" entered in the Protocol Registration and Results System (PRS) record.