| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Coronary spasm is a common cause of ischemic heart disease in Japanese. We have recently reported that oxidative stress is involved in the pathogenesis of coronary spasm, and that this disorder has genetic risk factors. By genetic analysis of endothelial nitric oxide synthase (eNOS) in coronary spasm patients, we found a missense Glu298Asp mutation in exon 7 and a T^<-786>→C mutation in the 5'-flanking region, and concluded that the mutations are significantly associated with coronary spasm.
By functional analysis, we revealed that each mutation was not merely a maker of coronary spasm, but showed functional abnormality. In the T^<-786>→C mutation, a transcription factor, a replication protein A-1 (RPA-1) binds to the variant sequence, reducing transcription of the eNOS gene. Also, regarding Glu298Asp, it has been clarified that intracelluar processing differs by the wild type protein and the mutant type one ; the mutant protein is tended to be cleaved within a cell. This result suggest
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s that the Glu298Asp variant itself results in functional abnormality.
As it has been reported that another polymorphism, intron 4b/a, is linked to ischemic heart disease in Caucasians, we did a linkage analysis of all these mutations. We found that intron 4b/a is linked to the T^<-786>→C mutation, suggesting that the T^<-786>→C mutation underlies the functional characteristic of the intron 4a allele.
We have also reviewed association studies, of the T^<-786>→C and Glu298Asp mutations, with other cardiovascular diseases. Each mutation was associated with myocardial infarction ; further, the T^<-786>→C mutation was strongly associated with myocardial infarction without organic stenosis in coronary arteries. We noted that the Glu298Asp mutation was significantly associated with essential hypertension, although the T^<-786>→C mutation was not. We have also reported that Glu298Asp is associated with severe preeclampsia, suggesting that eNOS gene mutations are associated with some diseases having underlying oxidative stress. Less
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