Identification of genetic susceptibility for cardiovascular disease : two large genetic epidemiological study with cohort base

心血管疾病遗传易感性的识别：两项大型队列基础遗传流行病学研究

• 批准号: 10307018
• 负责人: OGIHARA Toshio
• 金额: $ 24.26万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10307018/
• 关键词: polymorphism; pharamacogenetics; renin-angiotensin system; SNPs; hypertension; cohort study; lacunar infarction; genetic susceptibility; レニンーアンジ オテンシン系; レニンーアンジオテンシン系; 老年者; 遺伝疫学; 本態性高血圧症; 遺伝的異質性; アンジオテンシン変換酵素; 地域住民検診; 疾患感受性遺伝子

To identify causal genes of cardiovascular disease (hypertension, ischemic heart disease), we carried out a genetic investigation using candidate gene approach. In a cohort study using a large number of urban residents (S study), deletion/insertion polymorphism of angiotensin converting enzyme gene (ACE) was determined in 5,014 subjects. The deletion homozygote of ACE (ACE/DD) increased the risk for pertension with male specific manner in Japanese, which suggested the similarity in the obtained results between Japanese and Caucasians (Circulation, 2000). Another cohort study using a large number of subjects in a rural community in northern part of Japan (O study) showed a unique association between lacunar infarction or periventriular hyperintensity and angiotensinogen or angiotensin II type 1 receptor polymorphism. We also obtained several interesting results : GNB3 gene polymorphism was not associated with hypertension, and several polymorphisms were identified in the beta subunit of epithelial sodium channel gene. On the other hand, M235T polymorphism of angiotensinogen gene was not associated with plasma angiotensinogen concentration but with increased risk for essential hypertension, which suggested that the genotype-phenotype correlation did not directly reflect the expression level of angiotensinogen gene. In the pharmacogenetic investigation, ACE/DD attenuated the effect of antihypertensive therapy or improvement of restenosis of coronary artery after PTCA.We also proposed the advantage and disadvantage of the methods of genetic investigations.

为了确定心血管疾病(高血压、缺血性心脏病)的致病基因，我们使用候选基因方法进行了遗传学调查。在一项以大量城市居民为对象的队列研究中(S研究)，在5014名受试者中检测了血管紧张素转换酶基因的缺失/插入多态性。ACE纯合子缺失(ACE/DD)增加了日本男性特有方式高血压的风险，这表明日本人和高加索人的研究结果是相似的(循环，2000)。另一项队列研究使用了日本北部农村社区的大量受试者(O研究)，显示腔隙性脑梗塞或脑室周围高强度与血管紧张素原或血管紧张素II 1型受体多态之间存在独特的关联。我们还得到了一些有趣的结果：GNB3基因多态性与高血压无关，并且在上皮性钠通道基因的β亚基中发现了几个多态性。另一方面，血管紧张素原基因M235T多态与血浆血管紧张素原浓度无关，但增加了患高血压的风险，提示这种基因-表型相关性不能直接反映血管紧张素原基因的表达水平。在药物遗传学研究中，ACE/DD减弱了抗高血压治疗或改善PTCA术后冠状动脉再狭窄的效果，并提出了基因研究方法的优缺点。

项目成果

Higaki J,Ogihara T: "The deletion allele of angiotensin converting enzyme gene increases the risk of essential hypertension in Japanese males : The Suita Study"Circulation. 101. 2060-2065 (2000)

Higaki J，Ogihara T：“血管紧张素转换酶基因的缺失等位基因增加了日本男性患原发性高血压的风险：吹田研究”循环。

Katsuya T,Ogihara T: "Effects on antihypertensive drugs and gene variants in renin-angiotensin system"Hypertens Res. (in press). (2001)

Katsuya T，Ogihara T：“对抗高血压药物和肾素-血管紧张素系统基因变异的影响”Hypertens Res。

Higaki J, Ogihara T, et al.: "The deletion allele of angiotensin converting enzyme gene increases the risk of essential hypertension in Japanese males : The Suita Study"Circulation. 101. 2060-2065 (2000)

Higaki J、Ogihara T 等人：“血管紧张素转换酶基因的缺失等位基因增加了日本男性患原发性高血压的风险：吹田研究”循环。

Okamura A.,Higaki J.,Ogihara T.: "Pharmacogenetic analysis of the effect of angiotensin-converting enzyme inhibitor on restenosis after percutaneous transluminal coronary angioplasty"Angiology. 50. 811-822 (1999)

Okamura A.，Higaki J.，Ogihara T.：“血管紧张素转换酶抑制剂对经皮冠状动脉成形术后再狭窄影响的药物遗传学分析”血管学。

Yamada K, Miki T, Ogihara T: "All patients with Werner's syndrome are insulin resistant, but only those who also have impaired insulin secretion develop overt diabetes"Diabetes Care. 22. 2094-2095 (1999)

Yamada K、Miki T、Ogihara T：“所有维尔纳综合征患者都存在胰岛素抵抗，但只有那些胰岛素分泌也受损的患者才会发展为明显的糖尿病”糖尿病护理。