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

噻嗪敏感型钠氯协同转运体(TSC)是肾脏远端曲管顶膜上主要的氯化钠转运途径，可能参与盐敏感型高血压的发病机制。已知TSC突变导致Gitelman综合征，这是一种常染色体隐性遗传性肾小管疾病，其特征是由于肾脏钠消耗、低钾血症、代谢性碱中毒、低镁血症和正常钙性低钙尿而导致的低血压。吉特尔曼综合征被认为是盐敏感型高血压的镜像。我们对36例Gitelman‘S综合征患者进行了TSC基因突变分析，揭示了盐敏感型高血压的遗传背景。共发现19个突变，包括8个新突变：R261C、N406H、A523T、M672I、R1009Q、N1014K、第9外显子C缺失和第16外显子C缺失。东北地区北部仅有5例患者存在第16外显子C缺失，提示该突变可能是一种区域依赖性聚集。我们还研究了这些TSC突变和2711G/A(R904Q)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组。未发现TSC突变，2711G/A多态在高血压患者和正常血压人群中的基因频率和等位基因频率均无差异。此外，我们还对26例低钾血症(血钾浓度<3.5mmoL/L)患者进行了Tsc基因突变分析。结果发现3个突变：T180K、L849H和R919C。5名患者有杂合性突变，1名患者有复合杂合性突变。突变频率为23%，等位基因频率为13.5%。包括TSC在内的盐重吸收机制在盐敏感型高血压中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.