From the Department of Medicine and Clinical Science, Kyoto University
Graduate School of Medicine, Kyoto (Y.M., Y. Saito, N.K., S.K., M.H., M.I.,
K.K., E.O., I.H., N.T., T.A., N.A., Y.Y., T.Y., H.I., I.M., K.N.); the
Division of Cardiology, Kumamoto University School of Medicine, Kumamoto
(M.Y., Y. Shimasaki, M.N., H.Y.); and the Diagnostic Science Department,
Shionogi & Co, Ltd, Osaka (T.K., H.T.), Japan.
Correspondence to Yoshihiko Saito, MD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 6068397, Japan. E-mail yssaito{at}kuhp.kyoto-u.ac.jp
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.
© 1998 American Heart Association, Inc.
Scientific Contributions
Endothelial Nitric Oxide Synthase Gene Is Positively Associated With Essential Hypertension
Key Words: genes • nitric oxide synthase • hypertension, essential • polymorphism • genetics
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F. Soubrier Nitric Oxide Synthase Genes : Candidate Genes Among Many Others Hypertension, April 1, 1999; 33(4): 924 - 926. [Full Text] [PDF]
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N. Kato, T. Sugiyama, H. Morita, T. Nabika, H. Kurihara, Y. Yamori, and Y. Yazaki Lack of Evidence for Association Between the Endothelial Nitric Oxide Synthase Gene and Hypertension Hypertension, April 1, 1999; 33(4): 933 - 936. [Abstract] [Full Text] [PDF]
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R. E. Pratt and V. J. Dzau Genomics and Hypertension : Concepts, Potentials, and Opportunities Hypertension, January 1, 1999; 33(1): 238 - 247. [Abstract] [Full Text] [PDF]
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