Genetic Variants in the Epithelial Sodium Channel in Relation to Aldosterone and Potassium Excretion and Risk for Hypertension

Abstract

Abstract —Renin and aldosterone secretion is often lower in blacks than in whites, characteristics that resemble a milder form of Liddle syndrome in which a mutation in the amiloride-sensitive epithelial sodium channel (ENaC) of the kidney results in enhanced resorption of sodium. In the present study, we looked for evidence that the intrinsic level of ENaC activity is indeed higher in blacks than in whites. In overnight urine samples collected from young people (249 white and 181 black subjects, mean age 13.4 years), the urinary aldosterone/potassium ratio, which is typically very low in Liddle syndrome, was lower in blacks than in whites: 0.421±0.024 (mean±SE) versus 0.582±0.016 nmol/mmol ( P <0.0001). In addition, all but 1 of 5 molecular variants in ENaC were much more common in blacks than in whites. G442V in the β-subunit, present in 16% of the blacks and in only 1 white, was associated with parameters reflective of a greater Na retention and potentially a higher ENaC activity: a lower plasma aldosterone concentration ( P =0.070), a lower urinary aldosterone excretion rate ( P =0.052), a higher potassium excretion rate ( P =0.048), and a lower urinary aldosterone/potassium ratio ( P =0.027). In a second cohort consisting of 126 black and 161 white normotensive subjects and 232 black and 188 white hypertensive subjects, βG442V did not show a significant association with hypertension ( P =0.089). On the other hand, a variant that was twice as common in whites, αT663A, was associated with being normotensive both in blacks ( P =0.018) and in whites ( P =0.034). Expression of either βG442V or αT663A in Xenopus oocytes did not result in a change in basal Na current, consistent with the variants being in linkage disequilibrium with alleles at active loci. In conclusion, several lines of evidence are presented to suggest that ENaC activity is higher in blacks than in whites, which could contribute to racial differences in Na retention and the risk for hypertension.