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

原发性高血压易感基因的鉴定及个体化药物的建立

• 批准号: 14207035
• 负责人: OGIHARA Toshio
• 金额: $ 30.87万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207035/
• 关键词: gene polymorphism; disease susceptibility; cardiovascular disease; tailored medicine; hypertension; gene environmental interaction; salt sensitivity; obesity; 候補遺伝子; SNPs; TaqMan; 薬剤反応性; 環境・遺伝相互作用; 対立遺伝子; レニンーアンジオテンシン系; レニン-アンジオテンシン系

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.

原发性高血压是一种常见病，其病因尚不清楚。尽管基因环境相互作用在原发性高血压的发病机制中很重要，但相互作用的确切机制尚未阐明。使用候选基因方法，我们根据人类/基因组/基因分析研究的伦理准则进行了几项大型遗传流行病学研究（大坂研究、吹田研究和尼崎研究），结果揭示了几种基因与环境的相互作用。首先，通过血管紧张素原、α-内收素、醛固酮合酶和G蛋白β3亚基基因多态性等位基因频率的比较，我们指出日本人盐敏感等位基因的频率高于白种人。噻嗪类敏感的 NaCl 协同转运蛋白基因的遗传多态性（其中突变被认为是 Gitelman 综合征的遗传原因）也与女性原发性高血压的患病率有关。此外，亚甲基四氢叶酸还原酶基因多态性增加有吸烟习惯的女性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原发性高血压的高患病率显着相关。获得的结果表明根据基因多态性的差异进行个性化药物治疗或生活方式改变的重要性。此外，我们开发的遗传流行病学基础设施的完善对于未来的药物遗传学研究，例如HOMED-BP-GENE研究是有用的。

项目成果

Iwai N, Katsuya T, Ogihara T, et al.: "Association between SAH, an acyl-CoA synthetase gene, and hypertriglyceridemia, obesity, and hypertension"Circulation. 105(1). 41-47 (2002)

Iwai N、Katsuya T、Ogihara T 等人：“SAH、酰基辅酶 A 合成酶基因与高甘油三酯血症、肥胖和高血压之间的关联”循环。

Adiponectin 1164T mutation is associated with the metabolic syndrome and coronary artery disease.

脂联素1164T突变与代谢综合征和冠状动脉疾病相关。

• 发表时间: 2004
• 期刊: Journal of American College Cardiology 43
• 作者: Ochiai R;Imai M;Sugimoto K;Matsuo A;Takiuchi S;Motone M;Iwashima Y;Kamide K;Ji Q;Ohashi K
• 通讯作者: Ohashi K

Morimoto S, Katsuya T, Ogihara T, et al.: "Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients"Am J Med.. 112. 89-94 (2002)

Morimoto S、Katsuya T、Ogihara T 等：“血管紧张素转换酶基因的删除等位基因是老年患者肺炎的危险因素”Am J Med.. 112. 89-94 (2002)

Motone M, Katsuya T, Ogihara T, et al.: "Association between hepatocyte growth factor gene polymorphism and essential hypertension"Hypertens Res. (in press). (2004)

Motone M、Katsuya T、Ogihara T 等：“肝细胞生长因子基因多态性与原发性高血压之间的关联”Hypertens Res。

Matsubara M, Katsuya T, Ogihara T, et al.: "Angiotensin-converting enzyme I/D polymorphism and hypertension : the Ohsama study"J Hypertens. 20(6). 1121-1126 (2002)

Matsubara M、Katsuya T、Ogihara T 等人：“血管紧张素转换酶 I/D 多态性和高血压：Ohsama 研究”J Hypertens。