Identification of the susceptible gene responsible for essential hypertension and establishment of tailored medicine

高血压是一种常见病，其病因尚不清楚。虽然基因与环境的交互作用在高血压的发病机制中具有重要作用，但其确切的作用机制尚未阐明。采用候选基因的方法，在《人类/基因组/基因分析研究伦理指南》的指导下，进行了几项大规模的遗传流行病学研究(Ohasama研究、Suita研究和Amagasaki研究)，结果揭示了几个基因环境的相互作用。首先，通过比较血管紧张素原、α-内收蛋白、醛固酮合成酶和G蛋白β3亚单位基因的等位基因频率，指出日本人的盐敏感等位基因频率高于高加索人。硫氮化物敏感的氯化钠共转运体基因的遗传多态被认为是Gitelman综合征的遗传原因，也与高血压的患病率仅在女性有关。此外，在有吸烟习惯的女性中，亚甲基四氢叶酸还原酶基因多态性增加了颈动脉粥样硬化的风险，脂联素基因多态性和低脂联素血症与高血压的高患病率显著相关。这些结果提示，根据基因多态性的不同，个体化用药或生活方式改变的重要性。此外，我们开发的遗传流行病学的基础设施的改进对于未来的药物遗传学研究是有用的，例如人类BP基因研究。

Essential hypertension is a common disease and its cause is still unknown. Though the gene environmental interaction is important in the pathogenesis of essential hypertension, the precise mechanism of the interaction has not been elucidated yet. Using the candidate gene approach, we carried out several large genetic epidemiological studies (the Ohasama Study, the Suita Study and the Amagasaki Study) under the Ethics Guidelines of for Human/Genome/Gene analysis research, resulted that we revealed several gene environmental interactions. First of all, we pointed out the high frequency of salt sensitive alleles in Japanese than Caucasians according to the comparison in the allele frequency of angiotensinogen, alpha-adducin, aldosterone synthase and G protein beta 3 subunit gene polymorphisms. A genetic polymorphism of thiazide sensitive NaCl cotransporter gene, in which mutation was denoted as the genetic cause of Gitelman's syndrome, was also associated with the prevalence of essential hypertension only in females. In addition, methylenetetrahydrofolate reductase gene polymorphism increased the risk for carotid atherosclerosis in the females with smoking habit, and adiponectin gene polymorphism and hypoadiponectinemia were significantly associated with high prevalence of essential hypertension. The obtained results suggested the importance of personalized medication or life style modification according to the difference of their gene polymorphism. Furthermore, the infrastructure improvement of the genetic epidemiology that we developed is useful for future pharmacogenetic studies, such as HOMED-BP-GENE study.