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Identification of genetic factors responsible for the pathogenesis of essential hypertension

原发性高血压发病机制遗传因素的鉴定

基本信息

批准号：
13204050
负责人：
OGIHARA Toshio
金额：
$ 22.78万
依托单位：
OSAKA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

项目摘要

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.

原发性高血压是心血管疾病的主要危险因素，其病因尚不清楚。虽然基因与环境的相互作用在原发性高血压的发病中起着重要作用，但其确切机制尚未阐明。为了证明全基因组扫描，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> 10，000），结果发现了几个新的候选基因。利用候选基因的方法，我们进行了韩代研究和几个大型的遗传流行病学研究（S，O，A，TS），结果也揭示了一些基因-环境相互作用。首先，通过AGT、ADD 1、GNB 3、CYP 11 B2基因多态性的等位基因频率比较，指出日本人盐敏感等位基因的频率高于高加索人。噻嗪敏感性氯化钠协同转运蛋白基因的遗传多态性，其中突变被称为Gitelman综合征的遗传原因，也与原发性高血压的患病率仅在女性。此外，MTHFR基因多态性增加吸烟女性颈动脉粥样硬化的风险，ADRB 2和ET 1基因多态性与原发性高血压合并肥胖的高患病率显著相关。研究结果提示，根据基因多态性的差异，个体化用药或生活方式的改变是非常重要的。