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Olle Melander

Principal investigator

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Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure

Author

  • Cristiano Fava
  • Martina Montagnana
  • Lena Nilsson
  • Philippe Burri
  • Peter Almgren
  • A Jonsson
  • P Wanby
  • G Lippi
  • P Minuz
  • Lennart Hulthén
  • M Aurell
  • Olle Melander

Summary, in English

Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1 000 000, in Sweden, suggesting that similar to 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension
  • Department of Clinical Sciences, Malmö

Publishing year

2008

Language

English

Pages

413-418

Publication/Series

Human Molecular Genetics

Volume

17

Issue

3

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Medical Genetics

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 0964-6906