(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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M. E. Hyndman, H. G. Parsons, S. Verma, P. J. Bridge, S. Edworthy, C. Jones, E. Lonn, F. Charbonneau, and T. J. Anderson The T-786->C Mutation in Endothelial Nitric Oxide Synthase Is Associated With Hypertension Hypertension, April 1, 2002; 39(4): 919 - 922. [Abstract] [Full Text] [PDF]
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L. A. Hefler, C. B. Tempfer, M. T. Bashford, G. Unfried, R. Zeillinger, C. Schneeberger, H. Koelbl, F. Nagele, and J. C. Huber Polymorphisms of the angiotensinogen gene, the endothelial nitric oxide synthase gene, and the interleukin-1{beta} gene promoter in women with idiopathic recurrent miscarriage Mol. Hum. Reprod., January 1, 2002; 8(1): 95 - 100. [Abstract] [Full Text] [PDF]
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 C. K. Naber, D. Baumgart, C. Altmann, W. Siffert, R. Erbel, and G. Heusch eNOS 894T allele and coronary blood flow at rest and during adenosine-induced hyperemia Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1908 - H1912. [Abstract] [Full Text] [PDF]
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N. Jeerooburkhan, L. C. Jones, S. Bujac, J. A. Cooper, G. J. Miller, P. Vallance, S. E. Humphries, and A. D. Hingorani Genetic and Environmental Determinants of Plasma Nitrogen Oxides and Risk of Ischemic Heart Disease Hypertension, November 1, 2001; 38(5): 1054 - 1061. [Abstract] [Full Text] [PDF]
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G. Heusch, R. Erbel, and W. Siffert Genetic determinants of coronary vasomotor tone in humans Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1465 - H1468. [Full Text] [PDF]
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 B. C Kone Molecular biology of natriuretic peptides and nitric oxide synthases Cardiovasc Res, August 15, 2001; 51(3): 429 - 441. [Abstract] [Full Text] [PDF]
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 C. Tempfer, G. Unfried, R. Zeillinger, L. Hefler, F. Nagele, and J. C. Huber Endothelial nitric oxide synthase gene polymorphism in women with idiopathic recurrent miscarriage Hum. Reprod., August 1, 2001; 16(8): 1644 - 1647. [Abstract] [Full Text] [PDF]
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H. E. von der Leyen and V. J. Dzau Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation Circulation, June 5, 2001; 103(22): 2760 - 2765. [Full Text] [PDF]
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P. M. Spooner, C. Albert, E. J. Benjamin, R. Boineau, R. C. Elston, A. L. George Jr, X. Jouven, L. H. Kuller, J. W. MacCluer, E. Marban, et al. Sudden Cardiac Death, Genes, and Arrhythmogenesis : Consideration of New Population and Mechanistic Approaches From a National Heart, Lung, and Blood Institute Workshop, Part II Circulation, May 22, 2001; 103(20): 2447 - 2452. [Abstract] [Full Text] [PDF]
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 L. Hou, D. Osei-Hyiaman, H. Yu, Z. Ren, Z. Zhang, B. Wang, and S. Harada Association of a 27-bp repeat polymorphism in ecNOS gene with ischemic stroke in Chinese patients Neurology, February 27, 2001; 56(4): 490 - 496. [Abstract] [Full Text] [PDF]
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K. Okumura, T. Osanai, T. Kosugi, H. Hanada, H. Ishizaka, T. Fukushi, T. Kamada, T. Miura, T. Hatayama, T. Nakano, et al. Enhanced phospholipase C activity in the cultured skin fibroblast obtained from patients with coronary spastic angina: possible role for enhanced vasoconstrictor response J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1847 - 1852. [Abstract] [Full Text] [PDF]
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Y. Miyamoto, Y. Saito, M. Nakayama, Y. Shimasaki, T. Yoshimura, M. Yoshimura, M. Harada, N. Kajiyama, I. Kishimoto, K. Kuwahara, et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T->C mutation associated with coronary spastic angina Hum. Mol. Genet., November 1, 2000; 9(18): 2629 - 2637. [Abstract] [Full Text] [PDF]
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 G. Gaeta, M. De Michele, S. Cuomo, P. Guarini, M. C. Foglia, M. G. Bond, and M. Trevisan Arterial Abnormalities in the Offspring of Patients with Premature Myocardial Infarction N. Engl. J. Med., September 21, 2000; 343(12): 840 - 846. [Abstract] [Full Text] [PDF]
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Y. Miyao, K. Kugiyama, H. Kawano, T. Motoyama, H. Ogawa, M. Yoshimura, T. Sakamoto, and H. Yasue Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina J. Am. Coll. Cardiol., August 1, 2000; 36(2): 432 - 437. [Abstract] [Full Text] [PDF]
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A. Elbaz, O. Poirier, T. Moulin, F. Chedru, F. Cambien, and P. Amarenco Association Between the Glu298Asp Polymorphism in the Endothelial Constitutive Nitric Oxide Synthase Gene and Brain Infarction Stroke, July 1, 2000; 31(7): 1634 - 1639. [Abstract] [Full Text] [PDF]
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O. Hirashima, H. Kawano, T. Motoyama, N. Hirai, M. Ohgushi, K. Kugiyama, H. Ogawa, and H. Yasue Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: Possible role of reactive oxygen species J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1860 - 1866. [Abstract] [Full Text] [PDF]
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 M. Tesauro, W. C. Thompson, P. Rogliani, L. Qi, P. P. Chaudhary, and J. Moss Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: Cleavage of proteins with aspartate vs. glutamate at position 298 PNAS, March 14, 2000; 97(6): 2832 - 2835. [Abstract] [Full Text] [PDF]
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R. Busse and I. Fleming A critical look at cardiovascular translational research Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1655 - H1660. [Full Text] [PDF]
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T. F. Luscher and G. Noll Is It All in the Genes... ? : Nitric Oxide Synthase and Coronary Vasospasm Circulation, June 8, 1999; 99(22): 2855 - 2857. [Full Text] [PDF]
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S. Nasreen, T. Nabika, H. Shibata, H. Moriyama, K. Yamashita, J. Masuda, and S. Kobayashi T-786C Polymorphism in Endothelial NO Synthase Gene Affects Cerebral Circulation in Smokers: Possible Gene-Environmental Interaction Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 605 - 610. [Abstract] [Full Text] [PDF]
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T. Nakano, T. Osanai, H. Tomita, M. Sekimata, Y. Homma, and K. Okumura Enhanced Activity of Variant Phospholipase C-{delta}1 Protein (R257H) Detected in Patients With Coronary Artery Spasm Circulation, April 30, 2002; 105(17): 2024 - 2029. [Abstract] [Full Text] [PDF]
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