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Abstract-The T594M allele of the epithelial sodium channel ␤-subunit has been proposed as a gain-of-function mutation leading to salt-sensitive hypertension in blacks that is particularly responsive to the specific sodium channel antagonist amiloride. However, the positive associations derive from small convenience samples, and the amiloride challenge study lacked a control group. We determined whether the T594M allele was associated with hypertension and blood pressure (BP) response to amiloride in 2 well-characterized random population samples including 3137 Dallas County subjects and 1666 Jamaican blacks. In multivariate models, the T594M allele was not predictive of systolic BP (adjusted odds ratio for hypertension 1.1; 95% confidence interval, 0.7 to 1.8). Amiloride treatment did not lower the BP of 6 T594M heterozygotes significantly more than in 22 control subjects (Pϭ0.8). We conclude that the T594M allele does not contribute significantly to BP in blacks and does not predict a significantly superior response to amiloride therapy. Key Words: hypertension, genetic Ⅲ ion channels Ⅲ sodium P eople of African descent are particularly susceptible to developing salt-sensitive hypertension, but the molecular mechanisms are poorly understood. The renal epithelial sodium channel (ENaC) constitutes the final common pathway for the reabsorption of the final 2% of filtered sodium from the distal nephron. A missense mutation in the ␤-subunit of the human ENaC gene (T594M allele of SCNN1B or ␤-ENaC) has been found only in persons of African descent and has been implicated as a gain-of-function mutation causing impaired renal sodium excretion and salt-sensitive hypertension. 1-3 The allele was found to be present in 6% of blacks overall and to be highly enriched in a hypertensive clinic population compared with normotensive controls. 2 Additional evidence for an association with hypertension was reported in a larger clinic population. 4 However, the enthusiasm generated from these positive association studies 2,4,5 has been tempered by independent reports that failed to confirm such an association. 6,7 The conflicting data surrounding this allele might derive from inadequate sample size, sampling biases inherent in clinic populations, the variability in resting blood pressure (BP) over time, confounding effects of drug treatment, and the multiplicity of environmental exposures and signaling pathways involved in the regulation of resting BP.The BP responsiveness to certain drugs, which predominately target a single BP-regulating pathway, might link more directly with the genetic underpinnings of hypertension than resting BP alone. The potassium-sparing diuretic amiloride, a specific ENaC antagonist, is normally a weak antihypertensive agent but has been proposed as the ideal treatment for hypertension in blacks carrying the T594M allele. 3 In a study of 14 T594M heterozygotes with mild-to-moderate hypertension, amiloride monotherapy was as effective in controlling BP as usual empiric combination therapy with 2 or 3 stan...

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