Endothelial nitric oxide synthase gene is positively associated with essential hypertension

Yoshihiro Miyamoto, Yoshihiko Saito, Noboru Kajiyama, Michihiro Yoshimura, Yukio Shimasaki, Masafumi Nakayama, Shigeki Kamitani, Masaki Harada, Masahiro Ishikawa, Koichiro Kuwahara, Emiko Ogawa, Ichiro Hamanaka, Nobuki Takahashi, Toshihiko Kaneshige, Hiroshi Teraoka, Takashi Akamizu, Nobuyuki Azuma, Yasunao Yoshimasa, Takaaki Yoshimasa, Hiroshi ItohIzuru Masuda, Hirofumi Yasue, Kazuwa Nakao

Research output: Contribution to journalArticle

464 Citations (Scopus)

Abstract

Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n = 458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.

Original languageEnglish
Pages (from-to)3-8
Number of pages6
JournalHypertension
Volume32
Issue number1
Publication statusPublished - 1998 Jul
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type III
Genes
Introns
Odds Ratio
Confidence Intervals
Minisatellite Repeats
Muscle Spasticity
Genetic Association Studies
Genetic Predisposition to Disease
Essential Hypertension
Gene Frequency
Exons
Arterial Pressure
Japan
Myocardial Infarction
Genotype
Hypertension
Population

Keywords

  • Genes
  • Genetics
  • Hypertension, essential
  • Nitric oxide synthase
  • Polymorphism

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Miyamoto, Y., Saito, Y., Kajiyama, N., Yoshimura, M., Shimasaki, Y., Nakayama, M., ... Nakao, K. (1998). Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension, 32(1), 3-8.

Endothelial nitric oxide synthase gene is positively associated with essential hypertension. / Miyamoto, Yoshihiro; Saito, Yoshihiko; Kajiyama, Noboru; Yoshimura, Michihiro; Shimasaki, Yukio; Nakayama, Masafumi; Kamitani, Shigeki; Harada, Masaki; Ishikawa, Masahiro; Kuwahara, Koichiro; Ogawa, Emiko; Hamanaka, Ichiro; Takahashi, Nobuki; Kaneshige, Toshihiko; Teraoka, Hiroshi; Akamizu, Takashi; Azuma, Nobuyuki; Yoshimasa, Yasunao; Yoshimasa, Takaaki; Itoh, Hiroshi; Masuda, Izuru; Yasue, Hirofumi; Nakao, Kazuwa.

In: Hypertension, Vol. 32, No. 1, 07.1998, p. 3-8.

Research output: Contribution to journalArticle

Miyamoto, Y, Saito, Y, Kajiyama, N, Yoshimura, M, Shimasaki, Y, Nakayama, M, Kamitani, S, Harada, M, Ishikawa, M, Kuwahara, K, Ogawa, E, Hamanaka, I, Takahashi, N, Kaneshige, T, Teraoka, H, Akamizu, T, Azuma, N, Yoshimasa, Y, Yoshimasa, T, Itoh, H, Masuda, I, Yasue, H & Nakao, K 1998, 'Endothelial nitric oxide synthase gene is positively associated with essential hypertension', Hypertension, vol. 32, no. 1, pp. 3-8.
Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M et al. Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension. 1998 Jul;32(1):3-8.
Miyamoto, Yoshihiro ; Saito, Yoshihiko ; Kajiyama, Noboru ; Yoshimura, Michihiro ; Shimasaki, Yukio ; Nakayama, Masafumi ; Kamitani, Shigeki ; Harada, Masaki ; Ishikawa, Masahiro ; Kuwahara, Koichiro ; Ogawa, Emiko ; Hamanaka, Ichiro ; Takahashi, Nobuki ; Kaneshige, Toshihiko ; Teraoka, Hiroshi ; Akamizu, Takashi ; Azuma, Nobuyuki ; Yoshimasa, Yasunao ; Yoshimasa, Takaaki ; Itoh, Hiroshi ; Masuda, Izuru ; Yasue, Hirofumi ; Nakao, Kazuwa. / Endothelial nitric oxide synthase gene is positively associated with essential hypertension. In: Hypertension. 1998 ; Vol. 32, No. 1. pp. 3-8.
@article{676d2868bcb04e178f8e7e1df4d2087d,
title = "Endothelial nitric oxide synthase gene is positively associated with essential hypertension",
abstract = "Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n = 458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95{\%} confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95{\%} confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.",
keywords = "Genes, Genetics, Hypertension, essential, Nitric oxide synthase, Polymorphism",
author = "Yoshihiro Miyamoto and Yoshihiko Saito and Noboru Kajiyama and Michihiro Yoshimura and Yukio Shimasaki and Masafumi Nakayama and Shigeki Kamitani and Masaki Harada and Masahiro Ishikawa and Koichiro Kuwahara and Emiko Ogawa and Ichiro Hamanaka and Nobuki Takahashi and Toshihiko Kaneshige and Hiroshi Teraoka and Takashi Akamizu and Nobuyuki Azuma and Yasunao Yoshimasa and Takaaki Yoshimasa and Hiroshi Itoh and Izuru Masuda and Hirofumi Yasue and Kazuwa Nakao",
year = "1998",
month = "7",
language = "English",
volume = "32",
pages = "3--8",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Endothelial nitric oxide synthase gene is positively associated with essential hypertension

AU - Miyamoto, Yoshihiro

AU - Saito, Yoshihiko

AU - Kajiyama, Noboru

AU - Yoshimura, Michihiro

AU - Shimasaki, Yukio

AU - Nakayama, Masafumi

AU - Kamitani, Shigeki

AU - Harada, Masaki

AU - Ishikawa, Masahiro

AU - Kuwahara, Koichiro

AU - Ogawa, Emiko

AU - Hamanaka, Ichiro

AU - Takahashi, Nobuki

AU - Kaneshige, Toshihiko

AU - Teraoka, Hiroshi

AU - Akamizu, Takashi

AU - Azuma, Nobuyuki

AU - Yoshimasa, Yasunao

AU - Yoshimasa, Takaaki

AU - Itoh, Hiroshi

AU - Masuda, Izuru

AU - Yasue, Hirofumi

AU - Nakao, Kazuwa

PY - 1998/7

Y1 - 1998/7

N2 - Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n = 458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.

AB - Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n = 458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.

KW - Genes

KW - Genetics

KW - Hypertension, essential

KW - Nitric oxide synthase

KW - Polymorphism

UR - http://www.scopus.com/inward/record.url?scp=0031902667&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031902667&partnerID=8YFLogxK

M3 - Article

C2 - 9674630

AN - SCOPUS:0031902667

VL - 32

SP - 3

EP - 8

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 1

ER -