Hannila-Handelberg T et al. (2005), Common variants of the beta and gamma subunits ...

XB-ART-2444

BMC Med Genet 2005 Jan 20;6:4. doi: 10.1186/1471-2350-6-4.

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Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension.

Hannila-Handelberg T , Kontula K , Tikkanen I , Tikkanen T , Fyhrquist F , Helin K , Fodstad H , Piippo K , Miettinen HE , Virtamo J , Krusius T , Sarna S , Gautschi I , Schild L , Hiltunen TP .

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Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC beta and gamma subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system. Initially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests. Two commonly occurring betaENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel gammaENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males (2.9%, p = 0.007) and blood donors (3.0%, p = 0.001). betaENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined (4.6% vs. 1.1%, p = 0.001). When expressed in Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the betaENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean (of supine and upright values) plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048). At least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of beta and gammaENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels.

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	Figure 1. Flow diagram of the recruitment of the patients with primary hypertension.
	Figure 2. Sequence analysis of the variant β and γENaC alleles. Chromatograms from both sequencing directions, nucleotide substitutions and predicted amino acid changes from three different hypertensive patients are shown.
	Figure 3. Renin values in postural test and after captopril administration. Individual plasma renin activities at supine, upright, and in response to captopril administration (CCT; 60-minute values) in carriers and non-carriers of the three ENaC variant alleles. The horizontal bars indicate the median renin values in each group.
	Figure 4. Renin responses in postural and captopril tests. Plasma renin responses (median and interquartile ranges) during the postural and captopril challenge tests (stimulated values minus baseline values in both cases) in carriers and non-carriers of the variant ENaC alleles.
	Figure 5. Channel activity of βENaC G589S and γENaC V546I variants in vitro. Comparison of channel activity of hENaC wild-type, and the βhENaC G589S and γhENaC V546I variants, when expressed in Xenopus oocytes. ENaC activity was measured as amiloride-sensitive Na+ current. Absolute currents were 5.09 ± 0.98 and 6.75 ± 1.23 μA for ENaC wt in the two series of experiments (number of oocytes given in parentheses).