(Circulation. 1999;100:1515-1520.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
A Common Variant of the Endothelial Nitric Oxide Synthase (Glu298
Asp) Is a Major Risk Factor for Coronary Artery Disease in the UK
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-545.)
From the Clinical Pharmacology Unit, University of Cambridge Clinical School, Box 110, Addenbrooke's Hospital, Cambridge, UK.
Correspondence to Professor M.J. Brown, Clinical Pharmacology Unit, Level 6, Centre for Clinical Investigation (ACCI), Addenbrooke's Hospital, Box 110, Cambridge CB2 2QQ, UK. E-mail mjb14{at}medschl.cam.ac.uk
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Abstract |
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Background—Endothelium-derived nitric oxide (NO) is synthesised from L-arginine by endothelial nitric oxide synthase (eNOS) encoded by the NOS 3 gene on chromosome 7. Because reduced NO synthesis has been implicated in the development of coronary atherosclerosis, which has a heritable component, we hypothesised that polymorphisms of NOS 3 might be associated with increased susceptibility to this disorder.
Methods and Results—Single-strand conformation polymorphism
analysis of NOS 3 identified a G
T
polymorphism in exon 7 of the gene which encodes a GluAsp amino
acid substitution at residue 298 of eNOS. We investigated the
relationship between this Glu298Asp variant and
atherosclerotic coronary artery disease (CAD) using 2
independent case-controlled studies. In the first study (CHAOS), cases
consisted of 298 unrelated patients with positive coronary
angiograms and controls were 138 unrelated healthy individuals
ascertained through a population health screen. In the second study
(CHAOS II), the cases were 249 patients with recent myocardial
infarction (MI), and a further 183 unrelated controls. There was an
excess of homozygotes for the Asp298 variant among patients
with angiographic CAD, and among patients with recent MI when compared
with their respective controls (35.9% versus 10.2%,
P<0.0001 in CHAOS, and 18.1% versus 8.7%,
P<0.02 in CHAOS II). In comparison to
Glu298 homozygotes, homozygosity for Asp298 was
associated with an odds ratio of 4.2 (95% CI, 2.3 to 7.9) for
angiographic CAD and 2.5 (95% CI, 1.3 to 4.2) for MI.
Conclusions—Homozygosity for a common NOS 3
polymorphism (894 GT) which encodes a Glu298Asp
amino acid substitution in eNOS is a risk factor for angiographic CAD
and recent MI in this population.
Key Words: coronary disease • myocardial infarction • nitric oxide • genetics
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Nitric oxide (NO) is synthesised from L-arginine and molecular oxygen1 by a family of 3 enzymes (the nitric oxide synthases [NOS]).2 In the endothelial cell, NO is synthesised by the endothelial (e) NOS encoded by a 26 exon gene (NOS 3) located on chromosome 7q35 to 36.3 In addition to relaxing vascular smooth muscle cells, endothelium-derived NO inhibits platelet4 and leukocyte5 adhesion to vascular endothelium, inhibits vascular smooth muscle cell migration6 and growth,7 and limits the oxidation of atherogenic low-density lipoprotein.8 These actions suggest that endothelial NO may have an important atheroprotective role beyond its effect on vessel tone and blood pressure and that an alteration in the activity of the vascular NO system could contribute to the pathogenesis of atherosclerosis.
Several observations support this view. In a rabbit model, long-term systemic inhibition of NO production with the NOS inhibitor L-NAME (at levels insufficient to increase blood pressure), enhances the formation of early atherosclerotic lesions.9 10 In humans, endothelium-dependent vasodilatory responses are defective in individuals with established atherosclerosis11 and in those with atherosclerotic risk factors.12 These changes are seen in coronary,11 brachial, and femoral vessels13 and may predate lesion formation, resulting in part from a reduction in bioavailable NO. Local14 or systemic15 administration of L-arginine ameliorates this endothelial dysfunction.
We hypothesised that functionally important variants of the NOS 3 could influence individual susceptibility to atherosclerosis by altering the amount of NO generated by the endothelium. This disease has an inherited component,16 although many genes are likely involved.17 We undertook a search for polymorphisms within the promoter and coding regions of NOS 3 and have identified several common polymorphisms with the potential to alter eNOS protein expression or function.18 We have briefly reported a negative case-control study with one of these variants in an East Anglian cohort of essential hypertensive patients.19 We now describe our detailed findings following genotyping for this same variant in 2 well-characterized cohorts of patients with coronary atherosclerosis recruited from the Cambridge Heart AntiOxidant Studies (CHAOS and CHAOS II).
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Coronary Artery Disease Subjects
The coronary artery disease (CAD) cases for the first study were drawn from the database of the Cambridge Heart Antioxidant Study (CHAOS).20 Details of the inclusion criteria and recruitment have been described previously. Briefly, 2002 patients with positive coronary angiograms were recruited during 1992 to 1994 at Papworth Hospital, Cambridge, for a randomized controlled clinical trial designed to test the hypothesis that high-dose vitamin E (
-tocopherol) would reduce the risk of myocardial
infarction (MI) in individuals with CAD. Blood samples for DNA
analysis were collected before randomization from most of the
patients entered after the first year of the study. Genotyping was
restricted to 298 unrelated white subjects aged <70 who had both
angiographically proven CAD (>50% stenosis affecting at least
1 vessel) and a suitable blood sample for DNA extraction. Information
on age, gender, blood pressure, cholesterol levels, drug
therapy, smoking status, and coexisting disease were obtained by a
specialist nurse on the day of angiography and stored on a computer
database.
Myocardial Infarction Subjects
The first 249 consecutive white individuals with acute MI
(defined as a history of chest pain associated with regional ST segment
elevation of 
1 mm in 2 or more adjacent limb leads or 2
mm in 2 or more adjacent precordial leads and/or a rise and fall in
serum creatine kinase measured over 48 hours) were recruited via
coronary care units of participating East Anglian hospitals to
a second randomized controlled trial (CHAOS II) examining the effect of
folate supplementation in the secondary prevention of MI. They provided
a blood sample for genotyping of the NOS 3 gene. Information
on age, gender, blood pressure, cholesterol levels, drug
therapy, smoking status, and coexisting disease were obtained at the
acute admission and stored on a computer database.
Healthy Controls
Thirty-two thousand healthy East Anglian subjects aged 40 to 69
years with no history of cardiovascular or other
disease were identified between 1990 and 1994 from general practice
registers; the subjects were invited for health screening at one of 43
health centers where information on diet, smoking habits, alcohol
consumption, and family history of illness was obtained. Casual blood
pressure (mean of 2 readings) was recorded, and a random
cholesterol level was measured from a sample of
finger-prick blood using a Reflotron analyser (Boehringer
Mannheim UK). Blood was also collected for DNA analysis
from subjects at the last 4 of the general practices.
Control Data Set for CHAOS
One hundred thirty-eight unrelated white control subjects who
did not differ significantly in terms of blood pressure,
cholesterol levels, or smoking status form the larger data
set were genotyped and used as a control group for the CAD
subjects in CHAOS. Because of the predominance of males and the high
frequency of smokers among the CHAOS cases, the controls could not be
matched completely for gender and smoking status.
Control Data Set for CHAOS II
Unrelated white control subjects from the original health screen
who matched CHAOS II patients most closely for age and sex but from
whom DNA was not originally collected were contacted and invited to
provide a blood sample for DNA analysis. One hundred
eighty-three individuals agreed to take part.
DNA Extraction and Genotyping
Genomic DNA was prepared from samples of whole blood by standard
methods. Oligonucleotide primers for polymerase chain
reaction (PCR) were designed using the published sequence of the human
NOS 3 gene (GenBank/EMBL L10693-L10709).3
Polymorphism analysis of the promoter region and exons was
undertaken in 64 chromosomes by PCR-single strand conformational
polymorphism analysis and DNA sequencing. Two variants were
identified in the promoter of the gene and one within the coding
region; all were single base substitutions18 (Figure 1
). The coding sequence variant was a
GT substitution in exon 7 (at position 894) in codon 298 which
alters the amino acid at this residue from Glu to Asp. In CHAOS,
genotyping of this polymorphism was performed by PCR amplification
of exon 7 with the flanking intronic primers
5'-CATGAGGCTCAGCCCCAGAAC-3' (sense) and 5'-AGTCAATCCCTTTGGTGCTCAC-3'
(antisense) followed by MboI restriction endonuclease
digestion for 16 hours at 37°C and resolution by electrophoresis on a
2.5% agarose gel. The 206 bp PCR product is cleaved into 119 bp
and 87 bp fragments in the presence of a T at nucleotide
894 (which corresponds to Asp298 but not in its
absence (Figure 2). In CHAOS II, samples
were also genotyped using allele-specific
oligonucleotide probes on the ABI 7700 TaqMan (Perkin
Elmer). The probes (5'-CCC CAG ATG
A(G/T)C CCC CAG AAC TCT;
wild type (G) FAM-labeled, mutant (T) TET-labeled) annealed to a 141 bp
fragment of exon 7 generated by PCR using a second pair of primers,
5'-GAA ACG GTC GCT TCG ACG T (forward) and 5'-ATC CCA CCC AGT CAA TCC
CT (reverse) according to the manufacturer's instructions.
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The CHAOS patients and their controls were also genotyped for a common polymorphism in the promoter (-922 A/G) by mismatch PCR (with primers 5'-ACCTTATCCTCCACTGCTTTTCAG-3' and 5'-GCTGGGGTTTGTAGTTGCGTG-3') followed by allele-specific endonuclease digestion with Cac 8I and agarose gel electrophoresis. We also genotyped a proportion of CHAOS patients (n=122) for the variable number tandem repeat (VNTR) polymorphism in intron 4, for which an association with CAD has been described.21
Power Calculations and Statistical Analysis
The allele frequency of the exon 7 variant was ascertained
initially in a pilot study of 50 cases with angiographically proven CAD
and 100 healthy controls. The frequency of the
Asp298 homozygotes and the
Asp298 allele was found to be 36% and 47%,
respectively, in cases versus 10% and 32%, respectively, in controls.
This suggested that only 221 cases and controls would be needed to
detect a 15% difference in the frequency of this allele with 90%
power at P=0.01. The number of cases was, however, increased
to permit analyses by gender, smoking status, and disease
severity. Genotype and allele frequencies were compared
between groups by 
2 analysis and odds
ratios, and 95% CIs were calculated. Continuous and non-normally
distributed variables were analyzed by Student's
t test and the Mann-Whitney U test, respectively.
Statistical analyses was performed using Minitab (Minitab Inc)
and P<0.05 was regarded as significant.
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Results |
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Case-Control Study of Angiographic CAD (CHAOS)
The frequency of the Glu298
Asp variant
was compared in a group of 298 patients with angiographically-proven
CAD and in 138 healthy control subjects from the same region of East
Anglia. The baseline demographic characteristics of these 2 groups are
shown in Table 1. There was an
excess of males and smokers among the CAD cases compared with controls,
in common with previous studies with this type of design. The
distribution of genotypes in the control group did not differ
significantly from that expected under Hardy-Weinberg equilibrium, but
there was a significant deviation from Hardy-Weinberg proportions in
the case group, with an excess of homozygotes for the
Asp298 variant among the CHAOS patients with CAD.
The proportion of Asp298 homozygotes in the
patients with CAD was 35.9% compared with 10.2% in controls
(P<0.0001, Table 2). In
comparison to Glu298 homozygotes, the odds ratio
for CAD was 4.2 (95% CI, 2.3 to 7.9) for Asp298
homozygotes and 0.7 (95% CI, 0.4 to 1.1) for heterozygotes. The
proportion of Asp298 homozygotes among CAD cases
was not significantly altered when subjects were subdivided by gender,
smoking status, or the number of diseased vessels (data not shown).
There were insufficient DNA samples available from patients suffering
MI or dying during follow-up to determine the predictive power of the
Glu298Asp variant for these end points.
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The controls and a subset of 122 CHAOS patients were also genotyped for the previously described 420 and 393 bp alleles of the intron 4 VNTR.21 The respective frequencies of these alleles were 0.84 and 0.16 in controls versus 0.83 and 0.17 in the patients with CAD (P=NS). The frequencies of the A and G alleles of the -922 A/G promoter polymorphism were 0.63 and 0.37, respectively, in the CHAOS patients compared with 0.66 and 0.33 in the controls (P=NS)
Case-Control Study of Myocardial Infarction (CHAOS II)
In the second study, the first 249 unrelated CHAOS II trial
recruits admitted to coronary care units in participating East
Anglian hospitals with acute MI, who provided a blood sample for DNA
analysis at admission, were genotyped for the
Glu298Asp polymorphism. An independent
group of 183 healthy controls from the original health screen who most
closely matched the MI cases for age, gender, and smoking status were
also genotyped. There was a small excess of smokers (28%)
among the cases (Table 3). In addition,
the average cholesterol level was lower among the cases
than controls in this study. Genotype frequencies were in
Hardy-Weinberg proportions in both the case and control groups. Once
again, there was an excess of individuals homozygous for
Asp298 among of MI cases (18.1%) compared with
healthy controls (8.7%) (P<0.02, Table 4). In comparison to
Glu298 homozygotes, the odds ratio for MI was 2.5
(95% CI,1.3 to 4.2) for Asp298 homozygotes and
1.2 (95% CI, 0.8 to 1.8) for heterozygotes (Table 5).
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Discussion |
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The major finding of this study was a strong association between a Glu298
Asp polymorphism of the eNOS and
the risk of CAD. This increased risk was confined to individuals
homozygous for the Asp298 variant and, in the
first CHAOS study, amounted to a >4-fold risk of CAD compared with
individuals homozygous for Glu298. In a second
independent study (CHAOS II), a significant excess of the
Asp298 homozygotes was also seen among
individuals with recent acute MI when compared with healthy controls
and the odds ratio for acute MI among Asp298
homozygotes was 2.5 times that of Glu298
homozygotes.
The cases for both studies were drawn from the same East Anglian
population but were otherwise ascertained independently. In the first
study, cases were recruited at the time of elective coronary
angiography at the regional cardiac center, in the second study, cases
were individuals with acute MI recruited at the time of admission to
the coronary care units of participating hospitals in the East
Anglian region. The difference between the 2 trials in terms of the
selection criteria for CAD may explain the apparently smaller excess of
Asp298 homozygotes in CHAOS II versus the
original CHAOS study, although confidence intervals for the odd ratios
for the 2 studies overlap (Table 5
). Recent reports from Japan
also support a role for the Glu298 Asp
polymorphism in the development of coronary
atherosclerosis and its complications, and suggest, as
does our study, that the excess risk is confined to Asp
homozygotes.22
Because NO is considered to be atheroprotective, the excess risk of CAD
or MI among Asp298 homozygotes may reflect a
reduction in the amount or activity of endothelial
nitric oxide synthase among such subjects. It is not clear from this
association study whether the Glu298Asp
polymorphism is a functional genetic variant or a marker for
another functional variant within this or an adjacent gene. Despite the
apparently conservative nature of a GluAsp amino acid substitution
there is ample evidence that such a substitution can substantially
alter protein function.23 Comparison with the recently
solved crystal structure of murine inducible nitric oxide synthase
(iNOS),24 suggests that residue 298 of human eNOS
(homologous with residue 308 of murine iNOS) is proximal to residues
critical for substrate binding (residues Glu371
in murine iNOS and Glu361 in human eNOS). Thus,
if the Asp298 variant of eNOS is associated with
altered NO synthesis, the mechanism is unlikely to have a direct effect
on substrate binding. One possibility is that this variant might
influence subcellular targeting or interaction with other regulatory
proteins such as caveolin-1.25
If the Asp298 variant of eNOS leads to an altered
NO synthesis, this could provide a mechanism for its increased
prevalence among CAD patients in the CHAOS study and might also explain
the unexpectedly large benefit of -tocopherol in
preventing MI.20 -tocopherol presumably
acts to prevent the accelerated NO destruction caused by free oxygen
radicals in the atherosclerotic vessel wall. Although a reduction in
endothelial production of NO may influence
progression of atherosclerosis in the coronary
artery wall, it may be less important for overall plaque stability and
therefore rupture. This may reflect the lower prevalence of
homozygosity for Asp298 among patients with acute
MI in CHAOS II compared with patients in the original CHAOS study.
However, another possible factor relates to the significantly lower
cholesterol levels in patients recruited into CHAOS II
compared with the population controls used. This presumably reflects
widespread use of cholesterol-lowering agents, especially
HMG-CoA reductase inhibitors, whose increased use succeeded
the first and preceded the second of our case-controlled studies.
We have found previously that the Glu298Asp
polymorphism is not associated with essential
hypertension19 in keeping with 2 negative linkage studies
of the NOS 3 gene in hypertensive sibling
pairs.26 27 This does not exclude the
Asp298 variant from encoding a hypofunctional
protein, because the levels of NOS inhibition required to accelerate
atherosclerosis in animal models do not alter systemic
blood pressure.9 10 It is also possible that the
Glu298Asp polymorphism has effects on eNOS
activity only when the enzyme is oxidatively stressed and/or the
tetrahydrobiopterin cofactor is rate-limiting, as may be the case in
atherosclerotic vessels.28 These hypotheses are currently
under examination in cells transfected with eNOS cDNAs carrying the 2
codon 298 variants.
The odds ratio for the Asp298 variant in the
first study is substantially greater than that reported previously for
other CAD candidate gene polymorphisms. Nevertheless, any findings
from genetic association studies should be interpreted with some
caution. Although the design provides a powerful tool for detecting the
effects of a disease-modifying gene (because of the positive
association which localizes the disease locus to within a few hundred
kilobases compared with several megabases for a locus identified by
linkage), such studies are sensitive to the effects of undetected
confounding or bias that may arise during the selection of either case
or control subjects. The former was reduced by recruiting cases and
controls from a single semirural region, where the predominantly white
population enabled recruitment to be restricted to a single ethnic
group. Despite this, the case group in the initial study were not in
Hardy-Weinberg equilibrium. This can arise because of a strong
association between an allele and disease state, undetected
population stratification, or genetic mistyping. The potential for
population stratification cannot be excluded completely, but the
possibility of a false positive association is substantially reduced by
the results of our second study (CHAOS II), involving independently
ascertained cases (albeit with a different
atherosclerosis phenotype) and controls from
the same geographical region. Further, in none of a 10% sample from
CHAOS, and in only 8 (out of 249) samples from CHAOS II was there a
discrepancy between the genotypes assigned by the PCR/RFLP and
allelic discrimination methods. This suggested a maximum error rate of
3% for the PCR/RFLP method of genotyping and could not explain the
observed excess of Asp298 homozygotes.
Reanalysis of the data in Table 4 to reflect these
changes still gave a significant excess of
Asp298/Asp298 homozygotes
in the CHAOS II sample (P=0.035).
There was the expected clustering of CAD risk factors among cases, and
our original control group could not be entirely matched for smoking
and sex. We did not detect, however, any association between the
Glu298Asp variant and any of these possible
confounders. Importantly, the frequency of the
Asp298 allele and corresponding homozygotes
among our controls was almost identical to that predicted from our
previous study in East Anglian hypertensive patients and to that
reported here in the new group of controls.19
A role for another NOS 3 polymorphism in CAD was also
reported recently by Wang et al, who showed that the risk of CAD was
increased 1.3-fold in smokers homozygous for the rare 393 bp VNTR
allele in intron 4 of the NOS 3
gene.21 This variant is unlikely to be functional,
however, but could be in linkage disequilibrium with another variant
lying elsewhere in the gene. Its relationship to the
Glu298Asp polymorphism remains to be to be
studied. We did not detect an increase in the frequency of the 393 bp
allele among cases from the first CHAOS study in comparison to
controls.
In summary, we have identified several polymorphisms in the
NOS 3 gene and one of these polymorphisms,
Glu298Asp, was found to be a major risk factor
for CAD in our white population from the East Anglian region. This
finding is potentially important but requires further confirmation in
other populations.
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Acknowledgments |
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We would like to thank Mathias Chiano of the MRC Biostatistics Unit, Addenbrooke's Hospital, Cambridge, for helpful statistical advice. This work was supported by a Project Grant from the British Heart Foundation and a Medical Research Council Clinical Training Fellowship (to A.D.H.).
Received December 8, 1998; revision received June 23, 1999; accepted June 23, 1999.
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C. Antoniades, D. Tousoulis, C. Vasiliadou, C. Pitsavos, C. Chrysochoou, D. Panagiotakos, C. Tentolouris, K. Marinou, N. Koumallos, and C. Stefanadis Genetic Polymorphism on Endothelial Nitric Oxide Synthase Affects Endothelial Activation and Inflammatory Response During the Acute Phase of Myocardial Infarction J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1101 - 1109. [Abstract] [Full Text] [PDF]
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V.-P. Valkonen, T.-P. Tuomainen, and R. Laaksonen DDAH gene and cardiovascular risk Vascular Medicine, July 1, 2005; 10(1_suppl): S45 - S48. [Abstract] [PDF]
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C. Fatini, F. Sofi, A. M. Gori, E. Sticchi, R. Marcucci, M. Lenti, A. Casini, C. Surrenti, R. Abbate, and G. F. Gensini Endothelial Nitric Oxide Synthase -786T>C, but Not 894G>T and 4a4b, Polymorphism Influences Plasma Homocysteine Concentrations in Persons with Normal Vitamin Status Clin. Chem., July 1, 2005; 51(7): 1159 - 1164. [Abstract] [Full Text] [PDF]
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 A. D. Shaw, A. A. Vaporciyan, X. Wu, T. M. King, M. R. Spitz, J. B. Putnam, and B. F. Dickey Inflammatory Gene Polymorphisms Influence Risk of Postoperative Morbidity After Lung Resection Ann. Thorac. Surg., May 1, 2005; 79(5): 1704 - 1710. [Abstract] [Full Text] [PDF]
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J. P Cooke ADMA: its role in vascular disease Vascular Medicine, May 1, 2005; 10(2_suppl): S11 - S17. [Abstract] [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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Y. Liu, K. P. Burdon, C. D. Langefeld, S. R. Beck, L. E. Wagenknecht, S. S. Rich, D. W. Bowden, and B. I. Freedman T-786C Polymorphism of the Endothelial Nitric Oxide Synthase Gene Is Associated with Albuminuria in the Diabetes Heart Study J. Am. Soc. Nephrol., April 1, 2005; 16(4): 1085 - 1090. [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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N. C. Serrano, J. P. Casas, L. A. Diaz, C. Paez, C. M. Mesa, R. Cifuentes, A. Monterrosa, A. Bautista, E. Hawe, A. D. Hingorani, et al. Endothelial NO Synthase Genotype and Risk of Preeclampsia: A Multicenter Case-Control Study Hypertension, November 1, 2004; 44(5): 702 - 707. [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. Cattaruzza, T. J. Guzik, W. Slodowski, A. Pelvan, J. Becker, M. Halle, A. B. Buchwald, K. M. Channon, and M. Hecker Shear Stress Insensitivity of Endothelial Nitric Oxide Synthase Expression as a Genetic Risk Factor for Coronary Heart Disease Circ. Res., October 15, 2004; 95(8): 841 - 847. [Abstract] [Full Text] [PDF]
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M. van Onna, A. A. Kroon, A. J.H.M. Houben, D. Koster, M. P.A. Zeegers, L. H.G. Henskens, A. W. Plat, H. E.J.H. Stoffers, and P. W. de Leeuw Genetic Risk of Atherosclerotic Renal Artery Disease: The Candidate Gene Approach in a Renal Angiography Cohort Hypertension, October 1, 2004; 44(4): 448 - 453. [Abstract] [Full Text] [PDF]
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U. Paradossi, E. Ciofini, A. Clerico, N. Botto, A. Biagini, and M. G. Colombo Endothelial Function and Carotid Intima-Media Thickness in Young Healthy Subjects Among Endothelial Nitric Oxide Synthase Glu298->Asp and T-786->C Polymorphisms Stroke, June 1, 2004; 35(6): 1305 - 1309. [Abstract] [Full Text] [PDF]
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J. P. Casas, L. E. Bautista, S. E. Humphries, and A. D. Hingorani Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease: Meta-Analysis of 26 Studies Involving 23028 Subjects Circulation, March 23, 2004; 109(11): 1359 - 1365. [Abstract] [Full Text] [PDF]
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M. A Schmidt, A. K Chakrabarti, C. Kehrer, D. Pfeninnger, R. D Brook, N. Kaciroti, C. Duvernoy, A. A Killeen, and S. Rajagopalan Interactive effects of the ACE DD polymorphism with the NOS III homozygous G849T (Glu298->Asp) variant in determining endothelial function in coronary artery disease Vascular Medicine, August 1, 2003; 8(3): 177 - 183. [Abstract] [PDF]
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J. Song, Y. Yoon, K. U. Park, J. Park, Y. J. Hong, S. H. Hong, and J. Q. Kim Genotype-specific Influence on Nitric Oxide Synthase Gene Expression, Protein Concentrations, and Enzyme Activity in Cultured Human Endothelial Cells Clin. Chem., June 1, 2003; 49(6): 847 - 852. [Abstract] [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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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. Paolo Rossi, M. Cesari, M. Zanchetta, S. Colonna, G. Maiolino, L. Pedon, M. Cavallin, P. Maiolino, and A. C. Pessina The T-786C endothelial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study J. Am. Coll. Cardiol., March 19, 2003; 41(6): 930 - 937. [Abstract] [Full Text] [PDF]
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J. Loscalzo Functional polymorphisms in a candidate gene for atherothrombosis: Unraveling the complex fabric of a polygenic phenotype J. Am. Coll. Cardiol., March 19, 2003; 41(6): 946 - 948. [Full Text] [PDF]
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M. G. Colombo, U. Paradossi, M. G. Andreassi, N. Botto, S. Manfredi, S. Masetti, A. Biagini, and A. Clerico Endothelial Nitric Oxide Synthase Gene Polymorphisms and Risk of Coronary Artery Disease Clin. Chem., March 1, 2003; 49(3): 389 - 395. [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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A.H. Gomma, M.A. Elrayess, C.J. Knight, E. Hawe, K.M. Fox, and S.E. Humphries The endothelial nitric oxide synthase (Glu298Asp and -786T>C) gene polymorphisms are associated with coronary in-stent restenosis Eur. Heart J., December 2, 2002; 23(24): 1955 - 1962. [Abstract] [PDF]
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C. Szabo, A. Zanchi, K. Komjati, P. Pacher, A. S. Krolewski, W. C. Quist, F. W. LoGerfo, E. S. Horton, and A. Veves Poly(ADP-Ribose) Polymerase Is Activated in Subjects at Risk of Developing Type 2 Diabetes and Is Associated With Impaired Vascular Reactivity Circulation, November 19, 2002; 106(21): 2680 - 2686. [Abstract] [Full Text] [PDF]
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F. L Ruberg and J. Loscalzo Prothrombotic determinants of coronary atherothrombosis Vascular Medicine, November 1, 2002; 7(4): 289 - 299. [Abstract] [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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C.P.M. Leeson, A.D. Hingorani, M.J. Mullen, N. Jeerooburkhan, M. Kattenhorn, T.J. Cole, D.P.R. Muller, A. Lucas, S.E. Humphries, and J.E. Deanfield Glu298Asp Endothelial Nitric Oxide Synthase Gene Polymorphism Interacts With Environmental and Dietary Factors to Influence Endothelial Function Circ. Res., June 14, 2002; 90(11): 1153 - 1158. [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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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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R. M Bell and D. M Yellon The contribution of endothelial nitric oxide synthase to early ischaemic preconditioning: the lowering of the preconditioning threshold. An investigation in eNOS knockout mice Cardiovasc Res, November 1, 2001; 52(2): 274 - 280. [Abstract] [Full Text] [PDF]
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M. Scherrer-Crosbie, R. Ullrich, K. D. Bloch, H. Nakajima, B. Nasseri, H. T. Aretz, M. L. Lindsey, A.-C. Vancon, P. L. Huang, R. T. Lee, et al. Endothelial Nitric Oxide Synthase Limits Left Ventricular Remodeling After Myocardial Infarction in Mice Circulation, September 11, 2001; 104(11): 1286 - 1291. [Abstract] [Full Text] [PDF]
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B. C Kone Molecular biology of natriuretic peptides and nitric oxide synthases Cardiovasc Res, August 15, 2001; 51(3): 429 - 441. [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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C. P. M. Leeson, M. Kattenhorn, R. Morley, A. Lucas, and J. E. Deanfield Impact of Low Birth Weight and Cardiovascular Risk Factors on Endothelial Function in Early Adult Life Circulation, March 6, 2001; 103(9): 1264 - 1268. [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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J. W. Knowles and N. Maeda Genetic Modifiers of Atherosclerosis in Mice Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2336 - 2345. [Abstract] [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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Y. Yoon, J. Song, S. H. Hong, and J. Q Kim Plasma Nitric Oxide Concentrations and Nitric Oxide Synthase Gene Polymorphisms in Coronary Artery Disease Clin. Chem., October 1, 2000; 46(10): 1626 - 1630. [Abstract] [Full Text] [PDF]
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J. P. Cooke Does ADMA Cause Endothelial Dysfunction? Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2032 - 2037. [Abstract] [Full Text] [PDF]
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H.D. White International differences: selection, noise, or real? Eur. Heart J., March 1, 2000; 21(5): 339 - 342. [PDF]
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