Elsevier

The Lancet

Volume 351, Issue 9113, 9 May 1998, Pages 1388-1392
The Lancet

Articles
Association of hypertension with T594M mutation in β subunit of epithelial sodium channels in black people resident in London

https://doi.org/10.1016/S0140-6736(97)07306-6Get rights and content

Summary

Background

Liddle's syndrome is a rare inherited form of hypertension in which mutations of the epithelial sodium channel result in increased renal sodium reabsorption. Essential hypertension in black patients also shows clinical features of sodium retention so we screened black people for the T594M mutation, the most commonly identified sodium-channel mutation.

Methods

In a case-control study, 206 hypertensive (mean age 48·0 [SD 11·8] years, men:women 80:126) and 142 normotensive (48·7 [7·4] years; 61:81) black people who lived in London, UK, were screened for T594M. Part of the last exon of the epithelial sodium-channel β subunit from genomic DNA was amplified by PCR. The T594M variant was detected by single-strand conformational polymorphism analysis of PCR products and confirmed by DNA sequencing.

Findings

17 (8·3%) of 206 hypertensive participants compared with three (2·1%) of 142 normotensive participants possessed the T594M variant (odds ratio [OR]=4·17 [95% Cl 1·12–18·25], p=0·029). A high proportion of participants with the T594M variant were women (15 of 17 hypertensive participants and all three normotensive participants), whereas women comprised a lower proportion of the individuals screened (61·2% hypertensive, 57·7% normotensive). However, the association between the T594M variant and hypertension persisted after adjustment for sex and body-mass index (Mantel-Haenszel OR=5·52 [1·40–30·61], p=0·012). Plasma renin activity was significantly lower in 13 hypertensive participants with the T594M variant (median=0·19 ng mL−1 h−1) than in 39 untreated hypertensive individuals without the variant (median=0·45 ng mL−1 h−1, p=0·009).

Interpretation

Among black London people the T594M sodium-channel β subunit mutation occurs more frequently in people with hypertension than those without. The T594M variant may increase sodium-channel activity and could raise blood pressure in affected people by increasing renal tubular sodium reabsorption. These findings suggest that the T594M mutation could be the most common secondary cause of essential hypertension in black people identified to date.

Introduction

The importance of genetic predisposition in essential hypertension has long been established. In rat models of inherited hypertension, kidney cross-transplantation has shown that the kidney carries the genetic defect for high blood pressure which appears to be expressed as a difficulty in excretion of sodium.1 Circumstantial evidence suggests this may also be true in essential hypertension in human beings.2 The rare genetic causes of human hypertension all involve increased renal tubular sodium absorption, either indirectly through excess mineralocorticoid activity or directly as in Liddle's syndrome.3 Liddle's syndrome is caused by mutations of subunits of the epithelial sodium channel that result in increased sodium-channel activity in the distal renal tubule with excess sodium reabsorption.4, 5 This sodium retention causes the high blood pressure and the characteristic suppression of the renin-angiotensin system seen in Liddle's syndrome.6 High blood pressure in these patients responds well to reduction of salt intake or to amiloride, which acts specifically to reduce the activity of the abnormal channels.6

The clinical features of Liddle's syndrome overlap with those of some patients with essential hypertension. In particular, black patients with hypertension are known to be sensitive to changes in salt intake and have low plasma renin activity. Mutations in sodium-channel-subunit genes have been identified in a few patients with essential hypertension and almost all of them in patients of African descent.7 These mutations affect the same region of the sodium channel as occurs in Liddle's syndrome but differ as they result in a single aminoacid change rather than major truncation of the subunit. When the point mutations found in patients with essential hypertension are expressed in Xenopus oocytes most of them cause a non-significant increase in activity of sodium channels7 compared with what is observed when the mutations responsible for Liddle's syndrome are expressed.8 However, sodium-channel activity is increased in lymphocytes from patients with the threonine 594 methionine (T594M) point mutation of the sodium channel β subunit.9 Therefore, it is possible that this sodium-channel mutation in patients with essential hypertension could contribute to the rise in blood pressure by increasing renal tubular sodium reabsorption.

As yet, it is unknown whether these mutations occur more often in people with hypertension. Therefore we examined the frequency of the T594M point mutation, the most commonly identified sodium-channel mutation,7, 9 to see if it occurred more frequently in hypertensive than in normotensive black people.

Section snippets

Methods and participants

We did a case-control study of hypertensive and normotensive black individuals. Cases were taken from a group of unselected referrals to a hypertension clinic by local general practitioners (GPs) and comprised black patients with high blood pressure attending the clinic for the first time between February, 1995, and August, 1996, inclusively. Blood was collected from all cases during this time and a random number of samples were analysed. Controls were taken from a population-based,

Results

Characteristics of the two groups screened are summarised in table 1. Participants with hypertension were significantly heavier than normotensive participants and had higher BMI. The ethnic mix of participants in hypertensive and normotensive groups was similar, with 48·6% of individuals with hypertension and 48·6% of normotensive individuals having parents from Africa or born of African parents, and 45·6% of participants with hypertension and 45·8% of normotensive participants originating from

Discussion

In this case-control study of black London residents we have shown that the T594M variant of the β subunit of the epithelial sodium channel occurs significantly more frequently in individuals with hypertension (8·3%) than in those without (2·1%, p=0·029). The T594M variant in the individuals studied is associated with hypertension and could potentially be responsible for the development of high blood pressure in affected individuals.

The T594M mutation affects the last exon of the sodium channel

References (19)

There are more references available in the full text version of this article.

Cited by (236)

  • The spectrum of low-renin hypertension

    2020, Best Practice and Research: Clinical Endocrinology and Metabolism
  • Low-Renin Hypertension

    2019, Endocrinology and Metabolism Clinics of North America
    Citation Excerpt :

    It has also been hypothesized that single-nucleotide polymorphisms or rare variants in the same genes causing monogenic forms could also contribute to the development of low-renin essential hypertension by enhancing Na+ reabsorption, but without causing the classic monogenic syndromes, representing phenotypes with a milder spectrum of the classic forms.21 In particular, patients of African descent with low-renin hypertension demonstrate a high frequency of the pThr594Met substitution.22 These observations are supported by improvement in blood-pressure control in patients of African descent with low-renin hypertension treated with amiloride when compared with those treated following standard guidelines.23

  • Analyses of epithelial Na channel variants reveal that an extracellular β-ball domain critically regulates ENaC gating

    2019, Journal of Biological Chemistry
    Citation Excerpt :

    Other than well-defined Liddle syndrome mutations that disrupt or result in a loss of a Pro-Tyr (PY) motif in the C terminus of the β- or γ-subunit, correlating nonsynonymous ENaC variants that alter channel activity with predicted changes in blood pressure in humans has been challenging. This may reflect that fact that only two of the common ENaC nonsynonymous variants alter ENaC function in heterologous expression systems, and these have not been clearly linked to changes in blood pressure in humans (9–14). Other functional ENaC nonsynonymous variants that we and others have described are rare or of low-frequency (15–19).

  • Pathophysiological Links Between Diabetes and Blood Pressure

    2018, Canadian Journal of Cardiology
    Citation Excerpt :

    The epithelial sodium channel (ENaC) plays a critical role in sodium balance and hypertension.32 Mutations such as those involving the β subunit of ENaC occur more frequently in people with hypertension, and these mutations might result in increased renal tubular sodium reabsorption, contributing to the development of hypertension.33 Animal models of Zucker rats that were obese were reported to have increased renal expression of ENaC, which possibly contributes to sodium retention and obesity-associated hypertension.34

View all citing articles on Scopus
View full text