Clinical Significance of Sodium Metabolism-related Gene Polymorphisms in Salt-Sensitive Hypertension

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Thiazide-sensitive Na-Cl cotransporter (TSC) is the major NaCl transport pathway in the apical membrane of the renal distal convoluted tubule, which could be involved in the pathogenesis of salt-sensitive hypertension. Mutation of TSC is known to be responsible for Gitelman's syndrome, an autosomal recessive renal tubular disorder characterized by low blood pressure due to renal sodium wasting, hypokalemia, metabolic alkalosis, hypomagnesemia and normocalcemic hypocalciuria. Gitelman's syndrome is thought as a mirror image of salt-sensitive hypertension. We assessed mutational analysis of TSC gene in 36 patients with Gitelman' s syndrome, and this study revealed genetic backgrounds of salt-sensitive hypertension. We found 19 mutations include 8 novel mutations that were R261C, N406H, A523T, M672I, R1009Q, N1014K, deletion of C in the 9th exon and deletion of C in the 16th exon. Only 5 patients in northern area of Tohoku had deletion of C in the 16th exon suggesting that the specific mutation might be an area-dependent accumulation. We also investigated the association of those TSC mutations and 2711G/A (R904Q) polymorphism with hypertension. The case-control study consisted of 32 young hypertensive patients and 20 aged normotensive control subjects. We found no TSC mutations, and 2711G/A polymorphism was no differences in the genotype frequencies and the allele frequencies between hypertensives and normotensives. In addition, we assessed mutational analysis of TSC gene in 26 patients with hypokalemia (serum K concentration was under 3.5 mmol/l). As a result, we found 3 mutations, T180K, L849H and R919C. Five patients had heterozygous mutations and a patient had compound heterozygous mutations. The mutants frequency was 23%, and allele frequency was 13.5%. Further studies are needed to clarify clinical significance of NaCl reabsorption mechanisms including TSC in salt-sensitive hypertension.