Executive summary

The Seychelles Hypertension Study is a family-based study aimed at investigating the role of the amiloride-sensitive epithelial Na+ channel (ENaC) in the control of the blood pressure in the population of Seychelles - Indian Ocean – most of which is of African ancestry. Seychelles has a high prevalence of hypertension and cardiovascular diseases currently represent the main cause of death (36.6% in 1999). The second phase analyzes salt sensitivity through the blood pressure response to an ACE inhibitor and a diuretic in a crossover design, in relation to the genetic variants. The study is anticipated to include approximately 400 patients by mid 2001. The study is a joint project between the Ministry of Health of Seychelles and several departments of the University of Lausanne, Switzerland. It is funded by the Swiss National Science Foundation.

Investigators

Principal investigator: Michel Burnier (1)
Other investigators: Pascal Bovet (2,3), Vincent Mooser (1), Laurent Schild (4) and Tony Wong (2)
Study coordinator in Seychelles: Murielle Bochud (1,2,3)
Study staff in Seychelles: Catherine Falconnet (1,2) and Norma Both (2)


(1) University Hospital of Lausanne, Switzerland
(2) Ministry of Health, Seychelles
(3) Institute for Social and Preventive Medicine, Lausanne
(4) Pharmacology and Toxicology Institute, Lausanne

Funding agency and ethic clearance

The study is financed by the Swiss National Science Foundation, TANDEM No. 31-51115.97 (1999-2001). The study was approved by the Ministry of Health in Seychelles and by the ethics committee of the University of Lausanne, Switzerland. Participants are free to participate and give informed consent before participating to the study.

Objectives of the study

1. To determine the contribution of ENaC to the blood pressure phenotype in Seychelles
2. To characterize the plasma renin activity and plasma aldosterone profile, the renal hemodynamics and the renal sodium handling of hypertensive families in Seychelles
3. To analyze the blood pressure response to a diuretic and an ACE inhibitor, as an indirect measure of salt sensitivity, in relation to the ENaC variants
4. To analyze in Xenopus oocytes the functional properties of the detected genetic variants of ENaC
5. To extend the analysis to other genes involved in the control of sodium homeostasis

Description of the study

Background

ENaC is the rate limiting step of sodium reabsorption by the kidney. The genes of the three channel subunits are located in chromosome 12p13 for aEnaC and chromosome 16p12-13 for bEnaC and gEnaC. Mutations of the beta and gamma subunits, leading to an enhanced renal sodium reabsorption, were shown to be responsible for a rare autosomal dominant monogenic salt-sensitive form of hypertension -the Liddle’s syndrome- characterized by severe hypertension, hypokalemia, suppressed renin and aldosterone levels. Essential hypertension is a multifactorial disease with polygenic inheritance. In Black people, essential hypertension is characterized by clinical features of salt retention. Attenuated forms of Liddle’s syndrome could be implicated in essential hypertension, especially in black people (Baker et al., 1998, Persu et al., 1998).

Study design and analyses:

Part 1:
Since June 1999, families with at least 2 hypertensives siblings are identified through a multiple strategy involving primary health care centers, hypertension registers, cardiovascular screening programs in workplaces and screening from general public. Participants undergo detailed phenotyping screening including a determination of office and ambulatory blood pressure, renal hemodynamics (glomerular filtration rate, effective renal plasma flow) renal sodium handling, plasma renin activity and plasma aldosterone. A sib-pair linkage analysis - nonparametric or model-free approach- is used to study the implication of the candidate genes coding for ENaC through the determination of 5 polymorphic microsatellite markers (d12s356 and d12s164 for alpha, d16s412 and benacgt for beta, d16s420 for gamma). The functional properties of the genetic variants will then be analyzed in Xenopus oocytes. Other candidate genes involved in the control of sodium homeostasis will also be subsequently investigated.
Part 2:
Some eligible hypertensive patients enrolled in the first part are undergoing a study of the genetic variants according to their salt sensitivity. Salt sensitivity in this study is indirectly assessed by the blood pressure response to a diuretic and an ACE inhibitor given to participants along a crossover design (2 weeks washout phase, 4 weeks with either a diuretic or ACE inhibitor, 2 weeks washout, 4 weeks with the other medication).

Progress of the study

Part 1. By May 2001, 51 families have been fully phenotyped and recruitment is still ongoing. Genotyping analyses are ongoing. By May 2001, more than 300 participants had completed the study Part 1 and we expect a total of 400 patients to be included by the end of the study. The number of siblings per family ranges from 3 to 9. Parental genotype is available for 41% of families.

Part 2. By May, 35 patients were seen and we expect to include approximately 50 patients by the end of the study.

References:

Baker,E.H., Dong,Y.B., Sagnella,G.A. Rothwell,M., Onipinla,A.K., Markandu,N.D., Cappuccio,F.P., Cook,D.G., Persu,A., Jeunemaitre,X., Carter,N.D., MacGregor,G.A. (1998) Association of hypertension with T594M mutation in beta subunit of epithelial sodium channels in black people resident in London. Lancet 351: 1388-1392.

Persu,A.,Barbry,P., Bassilana,F., Houot,A.M., Mengual,R., Lazdunski,M., Corvol, P. and Jeunemaitre,X.(1998) Genetic analysis of the beta subunit of the epithelial Na+ channel in essential hypertension. Hypertension 32: 129-137.

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