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Human Molecular Genetics Advance Access originally published online on May 17, 2007
Human Molecular Genetics 2007 16(13):1630-1638; doi:10.1093/hmg/ddm112
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension

Cristina Barlassina1, Chiara Dal Fiume1, Chiara Lanzani3, Paolo Manunta3, Guia Guffanti1, Antonella Ruello1, Giuseppe Bianchi3, Lucia Del Vecchio1,2, Fabio Macciardi1 and Daniele Cusi1,2,*

1 Department of Sciences and Biomedical Technologies, University of Milan, Via Fantoli 16/15, 20090 Milan, Italy, 2 IRCCS Multimedica, 20099 Sesto San Giovanni, Italy and 3 Division of Nephrology, Dialysis and Hypertension, University ‘Vita e Salute’, San Raffaele Hospital, 20132 Milan, Italy

* To whom correspondence should be addressed. Tel: +39 (0) 250320959/46; Fax: +39 (0) 250320946; Email: cusi{at}unimi.it

Received January 30, 2007; Accepted April 25, 2007

Abnormal renal reabsorption of sodium (Na+) is likely to play a role in the pathogenesis of salt-sensitivity. In the kidney, chloride channels CLC-Ka (gene CLCNKA) and CLC-Kb (gene CLCNKB) and their subunit Barttin (gene BSND) have important effects on the control of Na+ and water homeostasis. We investigated if single nucleotide polymorphisms (SNPs) or haplotypes within CLCNKA, CLCNKB and BSND loci affect salt-sensitivity in hypertensive subjects. Associations between blood pressure (BP) change after Na+-load and 15 SNPs spanning the length of CLCNKA and CLCNKB and six SNPs spanning the length of BSND were studied in 314 never treated essential hypertensives who underwent an i.v. infusion of saline (300 mM NaCl in 2 l H2O in 120 min). Four SNPs were significantly associated with BP change after Na-load. Rs848307 (P = 0.0026) and rs1739843 (P = 0.0023) map upstream the 5' of CLCNKA. Non-coding Rs1010069 (P = 0.0006) and non-synonymous rs1805152 (Thr447Ala; P = 0.0078) map within CLCNKA. Moreover, basal plasma renin activity and heart rate (measured before Na-load) were significantly lower in patients carrying the alleles associated with the larger mean BP increase after Na-load, indicating that such alleles are associated with chronic volume expansion. This study supports the candidacy of CLCNKA as a new susceptibility gene for salt-sensitivity.


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