Human Molecular Genetics Advance Access published online on November 1, 2007
Human Molecular Genetics, 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, 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
Corresponding author/reprint requests: Cristiano Fava, Department of Biomedical and Surgical Sciences, Division of Internal Medicine C, University Hospital of Verona, Verona Phone: 0039-045-8124414Fax: 0039-045-508815E-mail: cristiano.fava{at}med.lu.se
Received August 28, 2007; Revised October 29, 2007; Accepted October 29, 2007
Gitelman's Syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NCCT gene encoding the kidney expressed NaCl co-transporter (NCCT), the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1.000.000, in Sweden, suggesting that approximately 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 mmHg vs. 123.2 ± 19.4; diastolic 62.5 ± 10.5 mmHg vs. 73.1 ± 9.4; 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 to 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.
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