T-786 → C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm

Masafumi Nakayama, Hirofumi Yasue, Michihiro Yoshimura, Yukio Shimasaki, Kiyotaka Kugiyama, Hisao Ogawa, Takeshi Motoyama, Yoshihiko Saito, Yoshihiro Ogawa, Yoshihiro Miyamoto, Kazuwa Nakao

Research output: Contribution to journalArticle

634 Citations (Scopus)

Abstract

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-922 → G, and T-1468 → A). 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-786 → C mutation resulted in a significant reduction in eNOS gene promoter activity (P < 0.05), whereas neither the A- 922 → G nor the T-1468 → A mutation had any affect. Conclusions - Taken together, these findings strongly suggest that the T-786 → C mutation in the eNOS gene reduces the endothelial NO synthesis and predisposes the patients with the mutation to coronary spasm.

Original languageEnglish
Pages (from-to)2864-2870
Number of pages7
JournalCirculation
Volume99
Issue number22
DOIs
Publication statusPublished - Jun 8 1999

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Nitric Oxide Synthase Type III
5' Flanking Region
Spasm
Mutation
Genes
Luciferases
Reporter Genes
Myocardial Ischemia
Molecular Biology
Logistic Models
Alleles
Regression Analysis
Control Groups
Incidence

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Nakayama, M., Yasue, H., Yoshimura, M., Shimasaki, Y., Kugiyama, K., Ogawa, H., ... Nakao, K. (1999). T-786 → C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation, 99(22), 2864-2870. https://doi.org/10.1161/01.CIR.99.22.2864

T-786 → C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. / Nakayama, Masafumi; Yasue, Hirofumi; Yoshimura, Michihiro; Shimasaki, Yukio; Kugiyama, Kiyotaka; Ogawa, Hisao; Motoyama, Takeshi; Saito, Yoshihiko; Ogawa, Yoshihiro; Miyamoto, Yoshihiro; Nakao, Kazuwa.

In: Circulation, Vol. 99, No. 22, 08.06.1999, p. 2864-2870.

Research output: Contribution to journalArticle

Nakayama, M, Yasue, H, Yoshimura, M, Shimasaki, Y, Kugiyama, K, Ogawa, H, Motoyama, T, Saito, Y, Ogawa, Y, Miyamoto, Y & Nakao, K 1999, 'T-786 → C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm', Circulation, vol. 99, no. 22, pp. 2864-2870. https://doi.org/10.1161/01.CIR.99.22.2864
Nakayama, Masafumi ; Yasue, Hirofumi ; Yoshimura, Michihiro ; Shimasaki, Yukio ; Kugiyama, Kiyotaka ; Ogawa, Hisao ; Motoyama, Takeshi ; Saito, Yoshihiko ; Ogawa, Yoshihiro ; Miyamoto, Yoshihiro ; Nakao, Kazuwa. / T-786 → C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. In: Circulation. 1999 ; Vol. 99, No. 22. pp. 2864-2870.
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T1 - T-786 → C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm

AU - Nakayama, Masafumi

AU - Yasue, Hirofumi

AU - Yoshimura, Michihiro

AU - Shimasaki, Yukio

AU - Kugiyama, Kiyotaka

AU - Ogawa, Hisao

AU - Motoyama, Takeshi

AU - Saito, Yoshihiko

AU - Ogawa, Yoshihiro

AU - Miyamoto, Yoshihiro

AU - Nakao, Kazuwa

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AB - 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-922 → G, and T-1468 → A). 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-786 → C mutation resulted in a significant reduction in eNOS gene promoter activity (P < 0.05), whereas neither the A- 922 → G nor the T-1468 → A mutation had any affect. Conclusions - Taken together, these findings strongly suggest that the T-786 → C mutation in the eNOS gene reduces the endothelial NO synthesis and predisposes the patients with the mutation to coronary spasm.

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