(Circulation. 1999;99:2864-2870.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
T-786
C Mutation in the 5'-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated With Coronary Spasm
From the Department of Cardiovascular Medicine, Kumamoto University School of Medicine; and the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (Y. Saito, Y.O., Y.M., K.N.), Japan.
Correspondence to Hirofumi Yasue, Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail yasue{at}kumamoto-u.ac.jp
Background—Coronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm.
Methods and Results—We searched for the possible mutations in the
endothelial nitric oxide synthase (eNOS) gene in
patients with coronary spasm. In this study, we demonstrate the
existence of 3 linked mutations in the 5'-flanking region of the eNOS
gene (T-786
C, A-922G, and
T-1468A). The incidence of the mutations was
significantly greater in patients with coronary spasm than in
the control group (P<0.0001). Multiple logistic
regression analysis with forward stepwise selection using the
environmental risk factors and the eNOS gene variant revealed that the
most predictive independent risk factor for coronary spasm was
the mutant allele (P<0.0001). As assessed by
luciferase reporter gene assays, the T-786C mutation
resulted in a significant reduction in eNOS gene promoter activity
(P<0.05), whereas neither the A-922G
nor the T-1468A mutation had any affect.
Conclusions—Taken together, these findings strongly suggest that
the T-786C mutation in the eNOS gene reduces the
endothelial NO synthesis and predisposes the patients
with the mutation to coronary spasm.
Key Words: spasm • nitric oxide • genes
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