Identification of genetic factors responsible for the pathogenesis of essential hypertension

高血压是心血管疾病的主要危险因素，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。为了演示全基因组扫描，我们向日本千年基因组计划高血压工作组提供了大量的人类DNA样本(n&gt；10,000)，结果发现了几个新的候选基因。利用候选基因方法，我们进行了韩代研究和几个大型遗传流行病学研究(S、O、A、TS)，结果还揭示了几个基因与环境的相互作用。首先，通过比较AGT、ADD1、GNB3、CYP11B2基因的等位基因频率，指出日本人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，MTHFR基因多态性增加了颈动脉粥样硬化的风险，ADRB2和ET1基因多态性与高血压合并肥胖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。

Essential hypertension is major risk for cardiovascular 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. To demonstrate the whole genome scan, we provided a lot of number of human DNA samples (n>10,000) to Hypertension Task Force of Japanese Millennium Genome Project, resulted that several new candidate genes were identified. Using the candidate gene approach, we carried out Handai Study and several large genetic epidemiological studies (S, O, A, TS), resulted that we also 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 AGT, ADD1, GNB3, CYP11B2 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, MTHFR polymorphism increased the risk for carotid atherosclerosis in the females with smoking habit, and ADRB2and ET1 gene polymorphisms were significantly associated with high prevalence of essential hypertension with obesity. The obtained results suggested the importance of personalized medication or life style modification according to the difference of their gene polymorphism.