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
We recently identified another variant of the eNOS gene within exon 7:
G to T conversion at nucleotide position 894 of eNOS cDNA
resulting in a replacement of glutamic acid by aspartic acid at codon
298 (Glu298Asp). This variant is associated with both coronary
spastic angina and myocardial infarction.8 9 To
further elucidate the genetic involvement of the eNOS gene in essential
hypertension, we examined the possible association between the
Glu298Asp variant and essential hypertension in two Japanese
populations. We also analyzed 3 other polymorphisms: 27-bp
tandem repeats in intron 4, A to C conversion in intron 18, and G to T
conversion in intron 23. We report here a significant association of
the Glu298Asp variant of the eNOS gene with essential hypertension in
Japanese subjects.
A second study population of 187 individuals (122 men, 65 women) with
essential hypertension and 223 normotensive control subjects (133 men,
90 women) was also selected at the Kumamoto University Hospital in
Kumamoto according to the same criteria as above. Kyoto and Kumamoto
are capital cities of two different prefectures located on different
islands of Japan; they are approximately 500 miles apart.
At the time of recruitment, informed consent was obtained from each
person according to a protocol approved by the Human Study Committee of
Kyoto University or Kumamoto University.
Identification of Genotype of eNOS Gene: Enzymatic
Amplification and RFLP Analysis of Glu298Asp Variant in Exon 7
of eNOS Gene
Detection of VNTRs in Intron 4 of eNOS Gene
ASO for Polymorphisms in Introns 18 and 23 of eNOS
Gene
Analysis of Differences in Clinical Parameters
Between Hypertensive and Normotensive Subjects
Analysis of Clinical Parameters Between
Normotensive and Hypertensive Subjects
Analysis of Genotype and Allele Frequencies for
eNOS Variants
Association Between Essential Hypertension and Polymorphisms of
eNOS Gene
We also investigated another Japanese population from Kumamoto
prefecture, which is 500 miles from the Kyoto prefecture. The same
genotypic and allelic disequilibrium in the Glu298Asp variant between
hypertensive and normotensive subjects was observed (Table 4
VNTRs polymorphism in intron 4 of the eNOS gene (eNOS4a/b) was
studied in 218 hypertensive and 240 normotensive control subjects in
the Kyoto group (Table 2
To determine whether a particular linkage was present between any
of these polymorphisms, we estimated eNOS haplotypes by combining
two distinct polymorphisms. As shown in the
Figure
We observed significant disequilibrium of the Glu298Asp variant of the
eNOS gene in two distinct populations from Kyoto and Kumamoto, Japan.
While the Japanese are thought to be racially homogeneous,
association studies are nevertheless liable to be biased owing to
uncontrolled stratification. However, the following results support the
interpretation that the observed association is not spurious:
significance was obtained in independent samples from two different
populations and frequencies of Glu298Asp are remarkably similar in both
populations. Bonnardeaux et al6 reported that the
polymorphisms in introns 18 and 23 were not associated with
essential hypertension. We therefore examined the two polymorphisms
in introns 18 and 23 in addition to a Glu298Asp missense variant. We
could find no association between hypertension and polymorphisms in
introns 18 and 23 in this Japanese population, which is
consistent with the previous study in whites reported by
Bonnardeaux et al.6 Although the frequencies of
polymorphisms in introns 18 and 23 were quite different between
Japanese and whites, an equilibrium between these alleles was
similarly obtained in both hypertensive and normotensive subjects in
both populations. These observations clearly indicate the validity of
the present Japanese population. Because Glu298Asp variant was not
linked with either polymorphism in intron 18 or intron 23, it is
reasonable to suppose that polymorphisms in introns 18 and 23 were
not associated with essential hypertension.
As for the case-control study of the eNOS gene on
cardiovascular diseases, Wang et
al7 reported an association of VNTRs
polymorphism located in intron 4 of the eNOS gene with
coronary artery disease related to smoking in whites in
Australia. We also examined the relation of the VNTRs polymorphism
to essential hypertension in our population, but we could not find a
significant association between them. Because the frequency of the
4a/298Asp haplotype is only 0.2% (Figure
Recently, three mendelian forms of human hypertension were recognized
in which a mutation in a single gene leads to elevated blood pressure
in a high proportion of affected subjects: glucocorticoid-remediable
aldosteronism,11 Liddle's syndrome
(pseudohypoaldosteronism),12 and the syndrome of
apparent mineralocorticoid excess.13 There have
been relatively few studies, however, examining the potential role of
candidate genes in essential hypertension. At present, among the
many candidate genes for a genetic basis of essential hypertension, the
genes of the renin-angiotensin system including
angiotensinogen,14
angiotensin-converting enzyme,15
angiotensin II type 1 receptor,16 and
the ANP genes17 are reported to be positively
associated with essential hypertension. Despite the promise of earlier
research, so far, studies of some common variants of the eNOS gene have
failed to clarify the nature of its involvement in essential
hypertension. In this study, we used a novel missense variant of the
eNOS gene to describe the association between the eNOS gene and
essential hypertension for the first time.
In this case, a nucleotide substitution at the open reading
frame causes amino acid substitution of glutamic acid to aspartic acid
at a codon in the 298th position. Therefore, we have only limited
information about whether this missense mutation gives rise to
functional alteration of eNOS enzymatic activity or is a genetic marker
associated with some causal loci. The Glu298Asp variant is not located
in any functional consensus sequence, but our computer analysis
revealed that the Glu298Asp mutation results in a conformation change
in the eNOS protein from helix to tight turn.18
We are now performing further studies for functional analysis
in vitro as well as measurement of NO production in vivo.
In contrast to the Glu298Asp variant, polymorphism in intron
23 and VNTRs polymorphism in intron 4 were significantly linked
(P<0.0001; Figure
In conclusion, we demonstrated that the Glu298Asp variant in the eNOS
gene is significantly associated with essential hypertension in the
Japanese population. These data indicate that the Glu298Asp variant of
the eNOS gene may be a possible genetic susceptibility factor for
essential hypertension. Further studies using sib-pair analysis
or linkage study are necessary for confirming the relationship between
essential hypertension and this variant.
Received January 5, 1998;
first decision February 13, 1998;
accepted February 25, 1998.
2.
Vallance P, Collier J, Moncada S. Effects of
endothelium-derived nitric oxide on
peripheral arteriolar tone in man. Lancet.. 1989;2:997–1000.[Medline]
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Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA,
Bevan JA, Fishman MC. Hypertension in mice lacking the gene for
endothelial nitric oxide synthase. Nature. 1995;377:239–242.[Medline]
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4.
Forte P, Copland M, Smith LM, Milne E, Sutherland J,
Benjamin N. Basal nitric oxide synthesis in essential hypertension.
Lancet. 1997;349:837–842.[Medline]
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5.
Taddei S, Virdis A, Mattei P, Ghiadoni L, Sudano I,
Salvetti A. Defective L-arginine/nitric oxide pathway in
offspring of essential hypertension patients. Circulation. 1996;94:1298–1303.
6.
Bonnardeaux A, Nandaud S, Charru A, Jeunemaitre X,
Corvol P, Soubrier F. Lack of evidence for linkage of the
endothelial cell nitric oxide synthase gene to
essential hypertension. Circulation. 1995;91:96–102.
7.
Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DE.
A smoking-dependent risk of coronary artery disease associated
with a polymorphism of the endothelial nitric oxide
synthase gene. Nat Med. 1996;2:41–45.[Medline]
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8.
Yasue H, Yoshimura M, Sugiyama S, Sumida H, Okumura K,
Ogawa H, Kugiyama K, Ogawa Y, Nakao K. Association of a point mutation
of the endothelial cell nitric oxide synthase gene with
coronary spasm. Circulation. 1995;92(suppl I):I-363.
Abstract.
9.
Shimasaki Y, Yasue H, Yoshimura M, Nakayama M,
Kugiyama K, Sugiyama S, Sumida H, Harada E, Ogawa Y, Nakao K.
Association between the Glu298Asp mutation of the nitric oxide synthase
gene and myocardial infarction in the Japanese. Circulation.
1996;94(suppl I): I-596. Abstract.
10.
Hill WG. Estimation of linkage disequilibrium in
randomly mating population. Heredity. 1974;33:229–239.[Medline]
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11.
Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick
S, Lalouel JM. A chimaeric 11 beta-hydroxylase/aldosterone
synthase gene causes glucocorticoid-remediable aldosteronism and human
hypertension. Nature. 1992;355:262–265.[Medline]
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12.
Hansson JH, Nelson-Williams C, Suzuki H, Schild L,
Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton RP.
Hypertension caused by a truncated epithelial sodium channel gamma
subunit: genetic heterogeneity of Liddle syndrome.
Nat Genet. 1995;11:76–82.[Medline]
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13.
Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC.
Human hypertension caused by mutations in the kidney isozyme of 11
beta-hydroxysteroid dehydrogenase. Nat Genet. 1995;10:394–399.[Medline]
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14.
Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP,
Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM.
Molecular basis of human hypertension: role of
angiotensinogen. Cell. 1992;71:169–180.[Medline]
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Zee RY, Lou YK, Griffiths LR, Morris BJ. Association of
a polymorphism of the angiotensin I-converting enzyme
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Angiotensin II type 1 receptor gene polymorphisms in
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© 1998 American Heart Association, Inc.
Scientific Contributions
Endothelial Nitric Oxide Synthase Gene Is Positively Associated With Essential Hypertension
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
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.
Key Words: genes • nitric oxide synthase • hypertension, essential • polymorphism • genetics
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
With a genetic
contribution of from 25% to 60%, human essential hypertension has a
genetic basis. Among persons younger than age 50 years, essential
hypertension occurs 3.8 times more often in those having two or more
first-degree relatives who developed high blood pressure before age
55.1 NO synthesis by the vascular
endothelium is important for the regulation of
vasodilator tone and the control of blood pressure in
humans.2 A recent study using mice with disrupted
eNOS gene revealed that eNOS function is required for vascular and
hemodynamic responses to acetylcholine and that the
disruption of the eNOS gene leads to
hypertension.3 Moreover, recent reports
demonstrate that whole-body NO production in patients with
essential hypertension is diminished under basal conditions, as
established by measurement of urinary and plasma
nitrate.4 In addition, the offspring of
hypertensive patients exhibit a reduced response to acetylcholine
linked to a defect in the NO pathway.5 These
results strongly implicate genetic alterations in the eNOS gene in the
pathogenesis of human essential hypertension. On the other hand, there
are no reports showing a positive association or linkage between eNOS
genotype and essential hypertension. Bonnardeaux et
al6 failed to demonstrate such an association or
linkage in white subjects either in a case-control study using two
polymorphisms in introns 18 and 23 of the eNOS gene (A to C and G
to T conversion, respectively) or by an affected sib-pair
analysis using CA repeat polymorphism. In other
cardiovascular diseases, however, Wang et
al7 examined the frequency of the 4b/4a VNTRs
polymorphism (4 or 5 repeats of 27 bp, respectively) in intron 4
and found a positive association between 4a polymorphism and
smoking-dependent risk of coronary artery disease.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Population: Hypertensive and Control Subjects
A total of 218 patients (112 men, 106 women) with essential
hypertension were selected from the outpatient clinics at Kyoto
University Hospital and its affiliated hospitals in Kyoto according to
the following criteria: (1) patient age >20
years, (2) onset of hypertension occurred at <60 years of age, (3)
established hypertension defined either as long-term treatment of the
disease, or in those previously untreated as
systolic/diastolic blood pressures >140/90
mm Hg on two consecutive visits, and (4) absence of secondary forms of
hypertension as determined through extensive workup. Blood pressure was
measured in the supine position using a sphygmomanometer. A group of
240 normotensive control subjects (135 men, 105 women) were selected
from the same clinics according to the following criteria: (1) subject
age >30 years, (2) systolic/diastolic blood
pressures <140/90 mm Hg, and (3) absence of antihypertensive
treatment.
We previously reported that the missense Glu298Asp mutation is a
common variant of the eNOS gene, and the specific genotype can
be identified with a PCR followed by RFLP using the restriction enzymes
MboI and BanII to digest mutant and wild
alleles, respectively. PCR primers were generated to amplify the
248-bp fragment encompassing the missense Glu298Asp variant (sense and
antisense primers were 5'-AAGGCAGGAGACAGTGGATGGA-3' and
5'-CCCAGTCAATCCCTTTGGTGCTCA-3', respectively). A guanine at
nucleotide position 894 results in a glutamic acid at amino
acid position 298, and a BanII restriction enzyme produces
two fragments of 163 bp and 85 bp in length. A thymine at
nucleotide position 894 results in an aspartic acid at
amino acid position 298, and a MboI restriction enzyme
produces two fragments of 158 bp and 90 bp in length. The restriction
digest products were analyzed by electrophoresis on 2.0%
agarose gels.
VNTRs in intron 4 of the eNOS gene were determined as previously
described by Wang et al.7
To determine the genotype of the eNOS gene according to
the polymorphism in introns 18 and 23, we performed ASO as
described in the previous report by Bonnardeaux et
al.6
Clinical parameters were analyzed in
hypertensive and normotensive control subjects; differences in the
frequencies of the following quantitative variables were tested
using unpaired, two-tailed Student's t test: age, systemic
blood pressure, diastolic blood pressure, body mass index,
plasma total cholesterol, HDL cholesterol,
creatinine, blood urinary nitrates, plasma renin activity,
plasma aldosterone concentrations, plasma ANP
concentrations, plasma BNP concentrations, an amplitude of
SV1+RV5 in ECG, and left
ventricular mass index.
All values for clinical parameters are expressed as
mean±SD. Except gender ratios, all clinical parameters
were compared with Student's t test. Gender ratios were
tested by 
2 test with 1 df. Values
of P<0.05 were considered statistically significant.
For each biallelic marker, allele frequencies were
calculated from the genotypes in the hypertensive and
normotensive groups. Deviation from Hardy-Weinberg equilibrium was
assessed using a 2 test with 1 df.
We estimated haplotype frequencies by the maximum-likelihood
method.10 Differences in autosomal dominant
genotype distribution between hypertensive and control subjects
were tested using Fisher's exact test. Differences in allele
frequencies between hypertensive and control subjects were also tested
using Fisher's exact test. Using Bonferroni-type correction,
P values of 0.0125 (= 0.05/4) or less, which correspond to
corrected P values of 0.05 or less, were considered
statistically significant for multiple testing. P values of
0.05 or less were considered significant for single testing. Linked
disequilibrium between the two polymorphisms we examined was
assessed using 2 test with 1 df,
and P values of 0.0083 (= 0.05/6) or less, which correspond
to corrected P values of 0.05 or less, were considered
statistically significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Clinical Characteristics of Study Subjects
The clinical characteristics of the 218 hypertensive and 240
normotensive subjects in Kyoto are summarized in Table 1
. No differences between the two groups
were noted with respect to age, body mass index, total serum
cholesterol levels, serum HDL cholesterol
levels, serum creatinine levels, plasma renin activity, or
plasma aldosterone concentrations. Serum uric acid levels
were significantly higher in the hypertensive group than in the control
group (P<0.01). Plasma ANP and BNP levels in the
hypertensive group were significantly higher than those in the control
group (P<0.05 and P<0.05, respectively).
Moreover, SV1+RV5 in the
ECG and left ventricular mass index estimated by
echocardiography were also significantly higher in
the hypertensive group than in the control group (P<0.0001
and P<0.0001, respectively). These data reflected cardiac
hypertrophy associated with hypertension.
View this table:
[in a new window]
Table 1. Clinical Parameters of Hypertensive and Normotensive
Subjects In Kyoto Group
Four types of polymorphism in the eNOS gene, including
Glu298Asp variant, 27-bp tandem repeats in intron 4, A to C conversion
in intron 18, and G to T conversion in intron 23, were analyzed
in hypertensive and normotensive subjects in Kyoto (Table 2). The genotype frequencies of
all 4 polymorphisms in each group satisfied the Hardy-Weinberg
equilibrium law. In the Kyoto population, only the Glu298Asp variant
showed a significant effect of genotype on hypertension
(P=0.0015), and its odds ratio was 2.3 (95% confidence
interval, 1.4 to 3.9); there was a significant increase in the allelic
frequency of the Glu298Asp variant in the hypertensive subjects
(P=0.0017). The allelic frequencies of the Glu298Asp variant
in normotensive and hypertensive subjects were 5.0% and 10.3%,
respectively. The effect of gender on the frequency of hypertension was
also considered. In both male and female populations, we observed
significant differences in genotype and allele frequencies
between hypertensive subjects and normotensive control subjects (Table 3). The odds ratio in both females and
males was 2.3. No significant gender-mediated preferential distribution
of this susceptibility variant was noted.
View this table:
[in a new window]
Table 2. Comparison of Genotype and Allele Frequencies for
Several Polymorphisms of eNOS Gene in Hypertensive and Normotensive
Subjects in Kyoto Group
View this table:
[in a new window]
Table 3. Comparison of Genotype and Allele Frequencies for
Glu298Asp Variants of eNOS Gene in Each Gender Population of Kyoto
Group ), and allelic frequencies of Glu298Asp
variant were similar in the Kyoto and Kumamoto populations. These
results demonstrate the positive association between the Glu298Asp
variant and hypertension in Japanese.
View this table:
[in a new window]
Table 4. Comparison of Genotype and Allele Frequencies for
Glu298Asp Variants of eNOS Gene in Two Distinct Areas in Japan 
). The genotype frequencies for
eNOS4b/b and eNOS4a/b plus eNOS4a/a in the normotensive population were
80.0% and 20.0%, respectively. Thus,
genotype frequency for eNOS4a/b plus eNOS4a/a was less than in
a white control population (33.4%).7 In the
Japanese population, there was no significant effect of this
genotype on the incidence of hypertension (P=0.339)
and no significant increase in the allelic frequency of eNOS4a in the
hypertensive subjects compared with the control group
(P=0.402). We also analyzed the A27 to C
polymorphism in intron 18 (a nucleotide substitution 27
bp downstream from exon 18) and the G10 to T polymorphism in intron
23 (a nucleotide substitution in 10 bp downstream from exon
23). Neither variant was reported to be associated with essential
hypertension in whites.6 Similarly, there was
also no significant increase of the allelic frequency of C27 or T10 in
Japanese hypertensive subjects (Table 2). , disequilibrium of Glu298Asp was
not linked to any other polymorphism investigated. Interestingly,
disequilibrium of eNOS 4a polymorphism was strongly linked to the
G10 to T polymorphism in intron 23 (P<0.0001). In other
words, the haplotype having both eNOS 4a and T10 in intron 23 was
detected at a frequency of 8.3%, while 4a polymorphism was found
at a frequency of only 11.4% (Figure). This suggests that 4a
polymorphism in introns 4 and 23 may be derived from the same
ancestor gene, while Glu298Asp variant in exon 7 occurred or was
integrated independently.
View larger version (36K):
[in a new window]
Figure 1. The eNOS gene structure is shown in the middle
(closed bar shows each exon) together with the four studied
polymorphisms: 4b/4a, 27-bp repeats (four repeats) in intron 4 of
the eNOS gene; Glu298Asp, missense variant in exon 7; A27 to C, A to C
nucleotide conversion in intron 18; and G10 to T, G to T
nucleotide conversion in intron 23. Percentile indexes
above the four polymorphisms (*) show allelic frequencies of each
polymorphism in this study. Percentile indexes ( 
) shown on the
bar between pairs of polymorphisms indicate the haplotype frequency
with the two polymorphisms. Each P value in
parenthesis was obtained by 2 test for linked
disequilibrium between the two polymorphisms. 
values show
deviation from linkage equilibrium (=h-p1p2; h, haplotype
frequency; p1, p2, frequencies of two alleles at two gene loci).
The lower open box indicates the cDNA structure and is divided by the
boundaries of the exons, which are numbered. Bold horizontal lines
below the open box indicate the putative functional domain: MYRIS,
myristoylation; HEME, heme binding portion; CaCM,
calmodulin binding portion; FMN, FMN binding;
FAD-P, FAD pyrophosphate binding; FLAVIN, flavin binding; FAD-I, FAD
isoalloxazine binding; NADPH-R, NADPH ribose binding; and NADPH-A,
NADPH adenine binding.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In the present study, we used the candidate gene approach to
explore whether the gene encoding eNOS, which is an important enzyme
producing endothelial-derived relaxing factor (NO), is
involved in the pathogenesis of human essential hypertension. We
demonstrated that there was a significant association of the Glu298Asp
polymorphism with essential hypertension in Japanese subjects. This
is the first report of a positive association between eNOS gene
polymorphism and essential hypertension. ), the putative functional
mutation related to VNTRs in intron 4 cannot be Glu298Asp variant or
any unknown functional locus related to the Glu298Asp variant. ). eNOS protein is a member of the
cytochrome P450 reductase-like NOS family and is composed of a heme
binding region, calcium/calmodulin binding region, and
NADPH-cytochrome P450 oxidoredactase. Because these compartments are
conserved in the NOS family (eNOS, inducible NOS, and neural NOS), gene
duplication and subsequent evolutionary divergence may have generated
NOS isoforms that are highly homologous in sequence and very closely
spaced on the chromosome. Glu298Asp variant in exon 7 is located in the
intermediate portion of the heme binding and
calcium/calmodulin binding sites, while intron 4 is next to
the heme binding site and intron 23 is located in the NADPH-cytochrome
P450 oxidoredactase. The degree of linkage disequilibrium among
polymorphisms in intron 4, exon 7, and intron 23 may be a clue to
understanding the evolutionary divergence of the eNOS gene.
Selected Abbreviations and Acronyms
ANP
=
atrial natriuretic peptide
ASO
=
allele-specific oligonucleotide hybridization
BNP
=
brain natriuretic peptide
eNOS
=
endothelial nitric oxide synthase
NO
=
nitric oxide
PCR
=
polymerase chain reaction
RFLP
=
restriction fragment length polymorphism
VNTRs
=
variable number of tandem repeats
Acknowledgments
This work was supported in part by research grants from the
Japanese Ministry of Education, Science, and Culture, the Japanese
Ministry of Health and Welfare, and grants from the Japanese
Cardiovascular Research Foundation, Takeda Science
Foundation, Smoking Research Foundation, Kanae Foundation of Research
for New Medicine, and Yamanouchi Foundation for Research on
Metabolic Disorders. We wish to thank Rie Ueno for her
technical assistance. We are indebted to a collaborator at Shionogi &
Co, Ltd, and especially to Takeshi Yoshioka and Hisanao Hiramatsu who
provided technical information. Drs Taroh Shirakawa and Norihiro Kato
kindly assisted us with the statistical analysis. The excellent
secretarial work of Tomoko Okumura and Miki Yamanaka is also
acknowledged.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Williams RR, Hunt SC, Hasstedt SJ, Hopkins PN, Wu
LL, Berry TD, Stults BM, Barlow GK, Schumacher MC, Lifton RP, Lalouel
JM. Are there interactions and relations between genetic and
environmental factors predisposing to high blood pressure?
Hypertension. 1991;18(suppl I):I-29–I-37.
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S. Wang, J. Xu, P. Song, Y. Wu, J. Zhang, H. Chul Choi, and M.-H. Zou Acute Inhibition of Guanosine Triphosphate Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Blood Pressure Hypertension, September 1, 2008; 52(3): 484 - 490. [Abstract] [Full Text] [PDF]
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G. F. Mitchell, C.-Y. Guo, S. Kathiresan, R. S. Vasan, M. G. Larson, J. A. Vita, M. J. Keyes, M. Vyas, C. Newton-Cheh, S. L. Musone, et al. Vascular Stiffness and Genetic Variation at the Endothelial Nitric Oxide Synthase Locus: The Framingham Heart Study Hypertension, June 1, 2007; 49(6): 1285 - 1290. [Abstract] [Full Text] [PDF]
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E. Zintzaras, G. Kitsios, and I. Stefanidis Endothelial NO Synthase Gene Polymorphisms and Hypertension: A Meta-Analysis Hypertension, October 1, 2006; 48(4): 700 - 710. [Abstract] [Full Text] [PDF]
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D. Gu, S. Su, D. Ge, S. Chen, J. Huang, B. Li, R. Chen, and B. Qiang Association Study With 33 Single-Nucleotide Polymorphisms in 11 Candidate Genes for Hypertension in Chinese Hypertension, June 1, 2006; 47(6): 1147 - 1154. [Abstract] [Full Text] [PDF]
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E. M. Garland, R. Winker, S. M. Williams, L. Jiang, K. Stanton, D. W. Byrne, I. Biaggioni, I. Cascorbi, J. A. Phillips III, P. A. Harris, et al. Endothelial NO Synthase Polymorphisms and Postural Tachycardia Syndrome Hypertension, November 1, 2005; 46(5): 1103 - 1110. [Abstract] [Full Text] [PDF]
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 A. Page, H. Reich, J. Zhou, V. Lai, D. C. Cattran, J. W. Scholey, and J. A. Miller Endothelial Nitric Oxide Synthase Gene/Gender Interactions and the Renal Hemodynamic Response to Angiotensin II J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3053 - 3060. [Abstract] [Full Text] [PDF]
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V.-P. Valkonen, T.-P. Tuomainen, and R. Laaksonen DDAH gene and cardiovascular risk Vascular Medicine, May 1, 2005; 10(2_suppl): S45 - S48. [Abstract] [PDF]
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M. D. Breyer, E. Bottinger, F. C. Brosius III, T. M. Coffman, R. C. Harris, C. W. Heilig, K. Sharma, and for the AMDCC Mouse Models of Diabetic Nephropathy J. Am. Soc. Nephrol., January 1, 2005; 16(1): 27 - 45. [Abstract] [Full Text] [PDF]
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S. Malhotra, J. Poole, H. Davis, Y. Dong, J. Pollock, H. Snieder, and F. Treiber Effects of NOS3 Glu298Asp Polymorphism on Hemodynamic Reactivity to Stress: Influences of Ethnicity and Obesity Hypertension, December 1, 2004; 44(6): 866 - 871. [Abstract] [Full Text] [PDF]
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W. Chen, S. R. Srinivasan, S. Li, E. Boerwinkle, and G. S. Berenson Gender-Specific Influence of NO Synthase Gene on Blood Pressure Since Childhood: The Bogalusa Heart Study Hypertension, November 1, 2004; 44(5): 668 - 673. [Abstract] [Full Text] [PDF]
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 M. Buraczynska, P. Ksiazek, W. Zaluska, T. Nowicka, and A. Ksiazek Endothelial nitric oxide synthase gene intron 4 polymorphism in patients with end-stage renal disease Nephrol. Dial. Transplant., September 1, 2004; 19(9): 2302 - 2306. [Abstract] [Full Text] [PDF]
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 T. Awata, T. Neda, H. Iizuka, S. Kurihara, T. Ohkubo, N. Takata, M. Osaki, M. Watanabe, Y. Nakashima, T. Sawa, et al. Endothelial Nitric Oxide Synthase Gene Is Associated With Diabetic Macular Edema in Type 2 Diabetes Diabetes Care, September 1, 2004; 27(9): 2184 - 2190. [Abstract] [Full Text] [PDF]
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 S. Cook, O. Hugli, M. Egli, B. Menard, S. Thalmann, C. Sartori, C. Perrin, P. Nicod, B. Thorens, P. Vollenweider, et al. Partial Gene Deletion of Endothelial Nitric Oxide Synthase Predisposes to Exaggerated High-Fat Diet--Induced Insulin Resistance and Arterial Hypertension Diabetes, August 1, 2004; 53(8): 2067 - 2072. [Abstract] [Full Text] [PDF]
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G. Gillerot, H. Debaix, and O. Devuyst Genotyping: a new application for the spent dialysate in peritoneal dialysis Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1298 - 1301. [Abstract] [Full Text] [PDF]
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S. Levesque, J.-M. Moutquin, C. Lindsay, M.-C. Roy, and F. Rousseau Implication of an AGT Haplotype in a Multigene Association Study With Pregnancy Hypertension Hypertension, January 1, 2004; 43(1): 71 - 78. [Abstract] [Full Text] [PDF]
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 E. Cediel, D. Sanz-Rosa, M. P. Oubina, N. de las Heras, F. R. G. Pacheco, O. Vegazo, J. Jimenez, V. Cachofeiro, and V. Lahera Effect of AT1 receptor blockade on hepatic redox status in SHR: possible relevance for endothelial function? Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R674 - R681. [Abstract] [Full Text] [PDF]
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N. Maruyama, Y. Yano, E. C. Gabazza, R. Araki, A. Katsuki, Y. Hori, K. Nakatani, Y. Sumida, and Y. Adachi Association Between Endothelial Nitric Oxide Synthase Glu298Asp Polymorphism and Postchallenge Insulin Levels in Nondiabetic Japanese Subjects Diabetes Care, July 1, 2003; 26(7): 2216 - 2218. [Full Text] [PDF]
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T. M. Seccia, G. P. Rossi, E. Noiri, T. Fujita, and K. Tokunaga Endothelial Nitric Oxide Synthase Gene Polymorphisms and Renal Survival * Response: Multifactorial Disease: Glu298asp of Endothelial Nitric Oxide Synthase Hypertension, June 1, 2003; 41 (6): e11 - e12. [Full Text] [PDF]
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L. D. Monti, C. Barlassina, L. Citterio, E. Galluccio, C. Berzuini, E. Setola, G. Valsecchi, P. Lucotti, G. Pozza, L. Bernardinelli, et al. Endothelial Nitric Oxide Synthase Polymorphisms Are Associated With Type 2 Diabetes and the Insulin Resistance Syndrome Diabetes, May 1, 2003; 52(5): 1270 - 1275. [Abstract] [Full Text] [PDF]
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 H. Grasemann, K. S. van's Gravesande, R. Buscher, J. M. Drazen, and F. Ratjen Effects of Sex and of Gene Variants in Constitutive Nitric Oxide Synthases on Exhaled Nitric Oxide Am. J. Respir. Crit. Care Med., April 15, 2003; 167(8): 1113 - 1116. [Abstract] [Full Text] [PDF]
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D. M. McNamara, R. Holubkov, L. Postava, R. Ramani, K. Janosko, M. Mathier, G. A. MacGowan, S. Murali, A. M. Feldman, and B. London Effect of the Asp298 Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure Circulation, April 1, 2003; 107(12): 1598 - 1602. [Abstract] [Full Text] [PDF]
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G. P. Rossi, S. Taddei, A. Virdis, M. Cavallin, L. Ghiadoni, S. Favilla, D. Versari, I. Sudano, A. C. Pessina, and A. Salvetti The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients J. Am. Coll. Cardiol., March 19, 2003; 41(6): 938 - 945. [Abstract] [Full Text] [PDF]
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H. Grasemann, K. S. van's Gravesande, R. Buscher, N. Knauer, E. S. Silverman, L. J. Palmer, J. M. Drazen, and F. Ratjen Endothelial Nitric Oxide Synthase Variants in Cystic Fibrosis Lung Disease Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 390 - 394. [Abstract] [Full Text] [PDF]
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T. Kimura, T. Yokoyama, Y. Matsumura, N. Yoshiike, C. Date, M. Muramatsu, and H. Tanaka NOS3 Genotype-Dependent Correlation Between Blood Pressure and Physical Activity Hypertension, February 1, 2003; 41(2): 355 - 360. [Abstract] [Full Text] [PDF]
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E. Noiri, H. Satoh, J.-i. Taguchi, S. V. Brodsky, A. Nakao, Y. Ogawa, S. Nishijima, T. Yokomizo, K. Tokunaga, and T. Fujita Association of eNOS Glu298Asp Polymorphism With End-Stage Renal Disease Hypertension, October 1, 2002; 40(4): 535 - 540. [Abstract] [Full Text] [PDF]
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A.J. Marian and E. Boerwinkle "Into Thin Air" and the Genetics of Complex Traits Circulation, August 13, 2002; 106(7): 768 - 769. [Full Text] [PDF]
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Y. Droma, M. Hanaoka, M. Ota, Y. Katsuyama, T. Koizumi, K. Fujimoto, T. Kobayashi, and K. Kubo Positive Association of the Endothelial Nitric Oxide Synthase Gene Polymorphisms With High-Altitude Pulmonary Edema Circulation, August 13, 2002; 106(7): 826 - 830. [Abstract] [Full Text] [PDF]
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G. Ghilardi, M. L. Biondi, M. DeMonti, M. Bernini, O. Turri, F. Massaro, E. Guagnellini, and R. Scorza Independent Risk Factor for Moderate to Severe Internal Carotid Artery Stenosis: T786C Mutation of the Endothelial Nitric Oxide Synthase Gene Clin. Chem., July 1, 2002; 48(7): 989 - 993. [Abstract] [Full Text] [PDF]
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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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 A. Persu, M. S. Stoenoiu, T. Messiaen, S. Davila, C. Robino, O. El-Khattabi, M. Mourad, S. Horie, O. Feron, J. -L. Balligand, et al. Modifier effect of ENOS in autosomal dominant polycystic kidney disease Hum. Mol. Genet., February 1, 2002; 11(3): 229 - 241. [Abstract] [Full Text] [PDF]
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M. D. Savvidou, P. J.T. Vallance, K. H. Nicolaides, and A. D. Hingorani Endothelial Nitric Oxide Synthase Gene Polymorphism and Maternal Vascular Adaptation to Pregnancy Hypertension, December 1, 2001; 38(6): 1289 - 1293. [Abstract] [Full Text] [PDF]
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H.-J. Hong, G. Hsiao, T.-H. Cheng, and M.-H. Yen Supplemention With Tetrahydrobiopterin Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats Hypertension, November 1, 2001; 38(5): 1044 - 1048. [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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H. Taniwaki, E. Ishimura, N. Matsumoto, M. Emoto, M. Inaba, and Y. Nishizawa Relations Between ACE Gene and ecNOS Gene Polymorphisms and Resistive Index in Type 2 Diabetic Patients With Nephropathy Diabetes Care, September 1, 2001; 24(9): 1653 - 1660. [Abstract] [Full Text] [PDF]
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H. Duplain, R. Burcelin, C. Sartori, S. Cook, M. Egli, M. Lepori, P. Vollenweider, T. Pedrazzini, P. Nicod, B. Thorens, et al. Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide SynthaseNote Added in Proof Circulation, July 17, 2001; 104(3): 342 - 345. [Abstract] [Full Text] [PDF]
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G. Kojda, Y. C. Cheng, J. Burchfield, and D. G. Harrison Dysfunctional Regulation of Endothelial Nitric Oxide Synthase (eNOS) Expression in Response to Exercise in Mice Lacking One eNOS Gene Circulation, June 12, 2001; 103(23): 2839 - 2844. [Abstract] [Full Text] [PDF]
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 G. Lembo, N. De Luca, C. Battagli, G. Iovino, A. Aretini, M. Musicco, G. Frati, F. Pompeo, C. Vecchione., and B. Trimarco A Common Variant of Endothelial Nitric Oxide Synthase (Glu298Asp) Is an Independent Risk Factor for Carotid Atherosclerosis Stroke, March 1, 2001; 32(3): 735 - 740. [Abstract] [Full Text] [PDF]
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L. A. Hefler, C. B. Tempfer, R. M. Moreno, W. E. O'Brien, and A. R. Gregg Endothelial-derived nitric oxide and angiotensinogen: blood pressure and metabolism during mouse pregnancy Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2001; 280(1): R174 - R182. [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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B. I. Freedman, H. Yu, P. J. Anderson, B. H. Roh, S. S. Rich, and D. W. Bowden Genetic analysis of nitric oxide and endothelin in end-stage renal disease Nephrol. Dial. Transplant., November 1, 2000; 15(11): 1794 - 1800. [Abstract] [Full Text] [PDF]
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H. Suzuki, S. Nagase, S. Kikuchi, Y. Wang, and A. Koyama Association of a Missense Glu298Asp Mutation of the Endothelial Nitric Oxide Synthase Gene with End Stage Renal Disease Clin. Chem., November 1, 2000; 46(11): 1858 - 1860. [Full Text] [PDF]
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T. Rankinen, T. Rice, L. Perusse, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard NOS3 Glu298Asp Genotype and Blood Pressure Response to Endurance Training : The HERITAGE Family Study Hypertension, November 1, 2000; 36(5): 885 - 889. [Abstract] [Full Text] [PDF]
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T. Yoshimura, M. Yoshimura, A. Tabatal, Y. Shimasaki, M. Nakayama, Y. Miyamoto, Y. Saito, K. Nakao, H. Yasue, and H. Okamura Association of the Missense Glu298Asp Variant of the Endothelial Nitric Oxide Syntahse Gene With Severe Preeclampsia Reproductive Sciences, July 1, 2000; 7(4): 238 - 241. [Abstract] [PDF]
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V. Martin, R. Bredoux, E. Corvazier, B. Papp, and J. Enouf Platelet Ca2+ATPases : A Plural, Species-Specific, and Multiple Hypertension-Regulated Expression System Hypertension, January 1, 2000; 35(1): 91 - 102. [Abstract] [Full Text] [PDF]
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H. Yu, B. I. Freedman, S. S. Rich, and D. W. Bowden Human Na+/H+ Exchanger Genes : Identification of Polymorphisms by Radiation Hybrid Mapping and Analysis of Linkage in End-Stage Renal Disease Hypertension, January 1, 2000; 35(1): 135 - 143. [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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I. Philip, G. Plantefeve, S. Vuillaumier-Barrot, E. Vicaut, C. LeMarie, D. Henrion, O. Poirier, B. I. Levy, J. M. Desmonts, G. Durand, et al. G894T Polymorphism in the Endothelial Nitric Oxide Synthase Gene Is Associated With an Enhanced Vascular Responsiveness to Phenylephrine Circulation, June 22, 1999; 99(24): 3096 - 3098. [Abstract] [Full Text] [PDF]
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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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