Identification of genetic factors responsible for the pathogenesis of coronary vasospasm, that is more prevalent in the Japanese, resulting in ischemic heart disease, and characterization of its molecular mechanism.

众所周知，导致缺血性心脏病的主要原因有两个，如心肌梗死。一个是冠状动脉粥样硬化，另一个是冠状动脉血管痉挛。先前的研究表明，日本人冠状动脉血管痉挛的患病率明显高于高加索人，这表明遗传因素在冠状动脉血管痉挛的发病机制中起着重要作用。本研究的具体目的是(1)确定与日本人冠状动脉血管痉挛发病相关的遗传因素，(2)根据已确定的遗传因素确定其分子机制。针对具体目标1，确定了三组患者：血管痉挛型心绞痛(VSA)组(n=162)、微血管心绞痛(MVA)组(n=61)和无反应者(NR，对照组)组(n=61)。对8个候选基因与这些患者进行了关联研究。与冠状动脉血管痉挛相关的两个基因突变/多态性是ROCK2(Rho Kinase基因)G930T和PON1(对氧磷酶1基因)A632G。我们以前发现的ROCK2 G930T突变可以通过错义突变改变功能。在这项研究中，我们已经证明了这种突变增加了Rho激酶的活性，可能导致血管痉挛。关于PON1 A632G多态，我们复制了该多态与VSA之间的关联，正如Ito等人之前所描述的那样。此外，该基因多态与MVA相关。这一发现是新颖的。与VSA呈显性关联，与MVA呈隐性关联，提示PON1 A632G多态导致血管痉挛的机制在VSA和MVA中可能不同。这项研究仍在进行中，为了达到我们的目标，有必要进行进一步的分析。

It is well known that there are two major causes for ischemic heart disease, such as myocardial infarction. One is coronary atherosclerosis, and another is coronary vasospasm. Previous studies have demonstrated a significantly higher prevalence of coronary vasospasm in the Japanese than in Caucasians, suggesting an important role of genetic factors in the pathogenesis of coronary vasospasm. The specific aims of this study are (1)to identify genetic factors responsible for the pathogenesis of coronary vasospasm in the Japanese, and (2)to characterize its molecular mechanism based on genetic factors identified. For the specific aim 1, three groups of patients have bees ascertained, vasospastic angina (VSA) group (n=162), microvascular angina (MVA) group (n=61), and non-responder (NR, control) group (n=61). An association study was carried out with eight candidate genes with these patients. Two gene mutation/polymorphism were associated with coronary vasospasm, ROCK2 (Rho kinease gene) G930T and PON1 (paraoxonase 1 gene) A632G. ROCK2 G930T mutation that we have identified previously could alter the function by missense mutation. In this study, we have demonstrated that this mutation increased Rho kinase activity, possibly resulting in vasospasm. Regarding PON1 A632G polymorphism, we have reproduced an association between this polymorphism and VSA as described previously by Ito et al. In addition, this polymorphism was associated with MVA. This finding is novel. An association with VSA was in dominant fashion, and that with MVA was in recessive fashion, indicating that mechanism leading to vasospasm with PON1 A632G polymorphism could be different between VSA and MVA. This study is still on going, and further analysis is necessary to reach our goal.