Endothelial nitric oxide synthase gene is positively associated with essential hypertension.
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.
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
Y
Y
Miyamoto
Y
Y
Saito
N
N
Kajiyama
M
M
Yoshimura
Y
Y
Shimasaki
M
M
Nakayama
S
S
Kamitani
M
M
Harada
M
M
Ishikawa
K
K
Kuwahara
E
E
Ogawa
I
I
Hamanaka
N
N
Takahashi
T
T
Kaneshige
H
H
Teraoka
T
T
Akamizu
N
N
Azuma
Y
Y
Yoshimasa
T
T
Yoshimasa
H
H
Itoh
I
I
Masuda
H
H
Yasue
K
K
Nakao
D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D016001:Confidence Intervals; D003627:Data Interpretation, Statistical; D004730:Endothelium, Vascular / Q000201:enzymology; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007438:Introns / Q000235:genetics; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics*; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase