Human Molecular Genetics Advance Access originally published online on November 1, 2007
Human Molecular Genetics 2008 17(3):413-418; doi:10.1093/hmg/ddm318
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Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure
1 Department of Clinical Sciences, Lund University, Malmö, Sweden 2 Department of Biomedical and Surgical Sciences, Division of Internal Medicine, University of Verona, Italy 3 Department of Morphological-Biomedical Sciences, Division of Clinical Chemistry, University of Verona, Verona, Italy 4 Department of Internal Medicine, Hospital of Jönköping, Jönköping, Sweden 5 Department of Internal Medicine, Hospital of Kalmar, Kalmar, Sweden 6 Department of Nephrology, Sahlgrenska Academy, Göteborg, Sweden
* To whom correspondence should be addressed at: Department of Biomedical and Surgical Sciences, Division of Internal Medicine C, University Hospital of Verona, Verona, Italy. Tel: +46 00390458124414; Fax: +46 0039045508815; Email: cristiano.fava{at}med.lu.se
Received August 28, 2007; Accepted October 29, 2007
Gitelma
s 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 
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.