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

为了确定心血管疾病（高血压、缺血性心脏病）的致病基因，我们采用候选基因方法进行了遗传调查。在一项包含大量城市居民的队列研究（S研究）中，对5014名受试者进行了血管紧张素转换酶基因（ACE）缺失/插入多态性检测。ACE纯合子的缺失（ACE/DD）增加了日本人男性特有方式的高血压风险，这表明日本人和白种人之间获得的结果相似（Circulation, 2000）。另一项在日本北部农村社区中使用大量受试者的队列研究（O研究）显示腔隙性梗死或室周高强度与血管紧张素原或血管紧张素II型1受体多态性之间存在独特的关联。我们还获得了几个有趣的结果：GNB3基因多态性与高血压无关，并且在上皮钠通道基因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多态性与血浆血管紧张素原浓度无关，但与原发性高血压的发病风险增加有关，提示基因型-表型相关性并不能直接反映血管紧张素原基因的表达水平。在药理学研究中，ACE/DD降低了PTCA后降压治疗或改善冠状动脉再狭窄的效果。我们还提出了遗传调查方法的优点和缺点。

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.