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