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Genetic Factors

A rapidly increasing body of evidence indicates that genetic factors affect blood pressure levels and the blood pressure response to a reduced sodium intake. Several genotypes that influence blood pressure have been identified. Most of these genotypes influence the renin-angiotensin-aldosterone axis or renal salt handling. Consequently, these genotypes likely affect salt sensitivity. In a line of investigation that focused on Mendelian diseases associated with either high or low blood pressure, six genes associated with higher blood pressure and another eight genes associated with lower blood pressure have been identified (Lifton et al., 2002). It is noteworthy that each of these genes regulates renal sodium chloride handling—mutations that increase net sodium chloride reabsorption raised blood pressure, while mutations that reduce sodium chloride reabsorption lowered blood pressure.

Glucocorticoid-remediable aldosteronism is an example of a disease associated with increased sodium reabsorption. In this autosomal-dominant condition associated with severe hypertension, chronic aldosterone secretion leads to increased intravascular volume. An example of a Mendelian disease associated with salt wasting is Gitelman’s syndrome. In analyses that compared blood pressure and urinary sodium excretion in individuals from a large group of related persons who carried zero, one, or two copies of the mutant gene, lower blood pressure was seen in those with two copies of the mutant gene (homozygotes) compared with those with no copy (wildtype) or one copy (heterozygotes). Both the homozygotes and heterozygotes consumed more salt than their wild-type relatives, indicating dietary compensation for their renal salt losses. Hence, although renal salt wasting leads to lower blood pressure in Gitelman’s syndrome, there was actually an inverse relationship between salt intake and blood pressure. These Mendelian conditions, while uncommon, demonstrate the importance of renal sodium chloride handling as a determinant of blood pressure.

Three trials have tested whether certain genotypes modify the blood pressure response to a reduced salt intake. In subgroup analyses (n = 1,509) from Phase II of the Trials of Hypertension Prevention (Hunt et al., 1998), a reduced sodium intervention significantly lowered the risk of developing hypertension over 3 years in those with the AA genotype of the angiotensinogen gene, but not those with the GG genotype. Those individuals with the AG genotype tended to have an intermediate phenotype. Because the GG genotype is uncommon in African Americans, this study focused only on



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