Abstract
BackgroundRare 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 βand γ subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system.MethodsInitially, 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.ResultsTwo commonly occurring βENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel γENaC 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). βENaC 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 βENaC 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).ConclusionsAt least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of β and γENaC, 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.
Highlights
Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome
Hundreds of case-control studies have suggested hypertension-related genetic variants of which only a few if any have tolerated replication analyses; it is possible that common variants of angiotensinogen [3], αadducin [4] and the G-protein β subunit [5] confer susceptibility to elevated blood pressure in at least some populations
Upon screening of exon 13 of the γENaC gene for mutations, one sample was detected with a novel point mutation changing codon 546 from GTC to ATC, which results in a substitution of isoleucine for valine (V546I)
Summary
Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. Recent large-scale searches for genes predisposing to hypertension, published as a recent series of articles [7,8,9,10,11], failed to identify definite linkage of hypertension to any chromosomal locus, some DNA regions showing suggestive linkage were disclosed. Reasons for these disappointing data were put on the account of the unsuitability of using a single-locus linkage strategy for a multifactorial genetic disease, inherent genetic heterogeneity of essential hypertension, and complex interplay of genetic and environmental factors underlying regulation of blood pressure variation [12]
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