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

噻嗪敏感性钠-氯协同转运蛋白（TSC）是肾远曲小管顶膜上主要的NaCl转运途径，可能参与盐敏感性高血压的发病机制。已知TSC的突变是Gitelman综合征的原因，Gitelman综合征是一种常染色体隐性肾小管疾病，其特征在于由于肾钠消耗引起的低血压、低钾血症、代谢性贫血、低镁血症和正常钙的低钙尿症。Gitelman综合征被认为是盐敏感性高血压的镜像。我们对36例Gitelman综合征患者进行了TSC基因突变分析，揭示了盐敏感性高血压的遗传背景。共发现19个突变，其中包括8个新突变，分别为R261 C、N406 H、A523 T、M672 I、R1009 Q、N1014 K、第9外显子C缺失和第16外显子C缺失。东北地区北方仅5例患者第16外显子C缺失，提示该特异性突变可能是一种区域依赖性累积。我们还研究了TSC突变和2711 G/A（R904 Q）多态性与高血压的关系。病例对照研究包括32例青年高血压患者和20例老年正常血压对照者。高血压组与正常血压组之间未发现TSC突变，2711 G/A多态性的基因型频率和等位基因频率无差异。此外，我们还对26例低钾血症（血清钾浓度低于3.5mmol/l）患者进行了TSC基因突变分析。结果，我们发现了3个突变，T180 K，L 849 H和R919 C。5例患者有杂合突变，1例患者有复合杂合突变。突变频率为23%，等位基因频率为13.5%。盐敏感性高血压中包括TSC在内的NaCl重吸收机制的临床意义尚需进一步研究。

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.