From the First Department of Internal Medicine, Kobe University School of
Medicine, Japan.
Correspondence to Seinosuke Kawashima, MD, The First Department of Internal Medicine, Kobe University School of Medicine, 7–5-1 Kusunoki-cho, Chuo-Ku, Kobe 650, Japan.
Methods and Results—We investigated whether these
polymorphisms were associated with risk of CAD by use of
restriction fragment length polymorphism (RFLP). The prevalence of
the TC+TT genotype of the C242T polymorphism was
significantly more frequent in control subjects (n=201) than in the
patients with CAD (n=201). The odds ratio of the TC+TT versus CC
genotype of the C242T polymorphism between control subjects
and case patients was 0.49 (95% CI, 0.28 to 0.87)
(P=.015). The prevalence of the genotypes of the
A640G polymorphism was not different between groups. The
association of C242T polymorphism of the p22 phox
gene with CAD was statistically significant and independent of other
risk factors.
Conclusions—The mutation of the potential heme-binding site of
the p22 phox gene may reduce susceptibility to CAD. Our
observations suggest that the C242T polymorphism of the p22
phox gene is a novel genetic marker that has a protective
effect on coronary risk.
Four types of allelic polymorphisms in the p22
phox gene have been reported.5 6 Among them,
C242T polymorphism of the p22 phox substitutes
histidine-72 by tyrosine located in the potential heme-binding sites,
and A640G polymorphism is located in the 3' untranslated region.
However, the clinical significance of these polymorphisms has never
been examined. The present study was designed to investigate
whether these polymorphisms were associated with risk of CAD by use
of RFLP.
Patients were considered smokers if their smoking index was >100. They
were considered to have hypertension if they met the criteria of the
World Health Organization or had already been treated with
antihypertensive drugs. They were considered to have
hypercholesterolemia if their fasting total
plasma cholesterol level was >220 mg/dL or they had
already been treated with cholesterol-lowering drugs. They
were defined as having diabetes if they met the diagnostic
criteria of the World Health Organization or were already under
treatment for diabetes.
Determination of Polymorphisms of p22 phox
by RFLP
A640G Polymorphism
The resulting fragments were separated by agarose gel electrophoresis
and identified by ethidium bromide staining
(Fig 1
Statistical Analysis
The distribution of genotypes and the frequency of alleles
of the polymorphisms of the p22 phox gene are summarized
in Table 2
Two kinds of NADH/NADPH oxidase system have been proposed to exist, ie,
phagocytic and vascular NADH/NADPH oxidase. In contrast to the
phagocytic NADPH oxidase, the molecular identity and clinical
significance of the vascular NADH/NADPH oxidase system are poorly
understood. p22 phox mRNA is expressed in phagocytes as well
as nonphagocytic cells, whereas other components are restricted to
phagocytic cells and are hardly detectable in nonphagocytic
cells.7 8 Ushio-Fukai et
al4 demonstrated that stable transfection of a
nearly full-length antisense fragment of the p22 phox gene
into VSMCs markedly decreased
·O2- production,
indicating that the p22 phox gene was a critical component
of ·O2-
production in this cell type.
Four types of polymorphism of the p22 phox gene are
reported, that is, C242T, C549T, G508A, and A640G. The C242T and C549T
polymorphisms affect amino acid sequence, whereas the G508A
polymorphism does not because of the degeneracy of the genetic
code, and the A640G polymorphism is located in the 3' untranslated
region. p22 phox, a heme-binding protein, contains two
histidine residues at amino acids 72 and 94, respectively,8
and these are the potential heme-binding sites. Because the C242T
polymorphism substitutes the histidine-72 to tyrosine residues,
this base substitution may have a direct functional role in the
association between the C242T polymorphism and coronary
risk. It is interesting to speculate that this mutation of the
p22 phox gene might modulate the activity and regulation of
NADH/NADPH oxidase, which leads to a decrease of oxidative stress in
the vasculature, and it might, in turn, reduce susceptibility to
CAD.
In conclusion, the prevalence of the TC+TT genotype of the
C242T polymorphism of the p22 phox gene in control
subjects was significantly more frequent than that in CAD patients. To
confirm that this polymorphism is a novel genetic marker for CAD,
investigations in a larger population and other ethnic populations are
necessary. Although some antioxidants have been reported to have
beneficial effects on CAD, the precise criteria for their use are not
fully determined. Some method to distinguish patients who have
genetically increased susceptibility to oxidative stress would be a
great advantage in treatment for CAD. Genetic investigation of the
genes related to oxidative stress, like this study, might provide clues
for determination of patients genetically susceptible to oxidative
stress.
Received September 11, 1997;
revision received October 31, 1997;
accepted November 3, 1997.
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RW. Angiotensin II stimulates NADH and NADPH oxidase
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Mohazzab-H KM, Kaminski PM, Wolin MS. NADH
oxidoreductase is a major source of superoxide anion in bovine
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Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N,
Griendling KK. p22 phox is a critical component of the
superoxide-generating NADH/NADPH oxidase system and regulates
angiotensin II-induced hypertrophy in vascular
smooth muscle cells. J Biol Chem. 1996;271:23317–23321.
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Dinauer MC, Pierce EA, Bruns GAP, Curnutte JT, Orkin
SH. Human neutrophil cytochrome b light chain (p22-phox): gene
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de Boer M, de Klein A, Hossle J-P, Seger R, Corbeel L,
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Jones SA, O'Donnell VB, Wood JD, Broughton JP, Hughes
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Parkos CA, Dinauer MC, Walker LE, Allen RA, Jesaitis
AJ, Orkin SH. Primary structure and unique expression of the
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© 1998 American Heart Association, Inc.
Brief Rapid Communications
Polymorphism of the NADH/NADPH Oxidase p22 phox Gene in Patients With Coronary Artery Disease
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Oxidative stress in the
vasculature has been implicated in the pathogenesis of coronary
artery disease (CAD). NADH/NADPH oxidase is a key enzyme of superoxide
production in the vasculature. p22 phox, an
essential component of NADH/NADPH oxidase, has four types of
polymorphism. The C242T polymorphism changes histidine-72 to
tyrosine, located in the potential heme-binding sites, whereas A640G
polymorphism is located in the 3' untranslated region.
Key Words: coronary disease • genes • risk factors • free radicals • stress
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Oxidative
stress in the vasculature induced by
·O2- has been implicated
in the pathogenesis of CAD.1 The sources of
·O2- in the vasculature
are diverse and include VSMCs, endothelial cells, and
macrophages. Although NADPH oxidase was originally described in
phagocytes, it has recently become evident that the NADH/NADPH oxidase
system is an important enzymatic origin of
·O2- in nonphagocytic
cells such as VSMCs and endothelial
cells.2 3 A recent investigation shows that
p22 phox, one of the electron transfer elements of NADPH
oxidase in phagocytes, is expressed in VSMCs and is a critical
component for ·O2-
generation in VSMCs.4
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
The study population was composed of 201 case patients and 201
control subjects; all subjects enrolled were Japanese. Case patients,
who had been admitted to Kobe University Hospital at the age of 
70
years, were clinically diagnosed as having CAD, and in all case
patients, significant coronary artery stenoses (>75%)
were demonstrated by coronary angiography. The control subjects
were selected from the inpatients of the hospital and matched with the
case patients for sex, and they had not had any symptoms of CAD or
peripheral atherosclerotic artery disease documented.
Written consent was obtained from every patient after a full
explanation of the study. The Ethics Committee of Kobe University
approved this study.
C242T Polymorphism
Because the C
T mutation of the C242T polymorphic site
produces the Rsa I digestion site, Rsa I RFLP was
used to analyze the polymorphism of the p22 phox
gene. The p22 phox gene containing this polymorphic site
was amplified from genomic DNA isolated from subjects by PCR. Digestion
of the PCR product (348 bp) by Rsa I makes 160- and
188-bp fragments in the CT mutation, whereas Rsa I does
not cut the PCR product in the wild type.
The AG mutation of this polymorphic site loses the
Dra III digestion site. The digestion of the PCR product
(258 bp) by Dra III makes 227- and 31-bp fragments in the
wild type, whereas Dra III does not cut the PCR product
in the AG mutation. 
). The results were confirmed by at
least two investigators, who did not know the origin of the genomic
DNA.
View larger version (25K):
[in a new window]
Figure 1. A, Rsa I RFLP of C242T polymorphism. DNA
fragment containing C242T polymorphic site of p22
phox gene was amplified from genomic DNA by PCR with sense
primer 5'-TGCTTGTGGGTAAACCAAGGCCGGTG-3' (F1) and antisense primer
5'-AACACTGAGGTAAGTGGGGGTGGCTCCTGT-3' (R1), then PCR product was
digested with Rsa I. C T mutation at
nucleotide 242 creates an Rsa I digestion
site, which digests 348-bp fragment into 160- and 188-bp fragments.
Bottom, Representative of 2% agarose gel
electrophoresis on Rsa I RFLP of p22 phox
gene. Lane 1, heterozygote of TC; lanes 2 and 3, homozygotes of CC;
lane 4, homozygote of TT. B, Dra III RFLP for A640G
polymorphism. DNA fragment containing A640G polymorphic site
was amplified from genomic DNA by PCR with sense primer
5'-AGCAGTGGACGCCCATCGAGCCCAA-3' (F2) and antisense primer
5'-CGCTGCGTTTATTGCAGGTGGGTGC-3' (R2), then PCR product (258 bp) was
digested with Dra III. Dra III digestion
of PCR product makes 227- and 31-bp fragments in wild type, whereas
Dra III does not cut PCR product in AG mutation.
Bottom, Representative of 2% agarose gel
electrophoresis on Rsa I RFLP of p22 phox
gene. Lane 1, homozygote of GG; lane 2, heterozygote of AG; lane 3,
homozygote of AA.
Data on age are presented as mean±SD, and the
difference in age was analyzed by unpaired Student's
t test. The differences in frequencies of smoking,
hypertension, hypercholesterolemia, diabetes
mellitus, and p22 phox genotypes were
analyzed by Fisher's exact test. Hardy-Weinberg equilibrium
was assessed by 
2 analysis.
Multivariate analyses were conducted with
multiple logistic regression methods, and an estimation of conditioned
relative risk and 95% CI was done.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The characteristics of the subjects are summarized in Table 1. There was no significant difference in
age between the groups. The coronary risk factors examined, ie,
smoking, hypercholesterolemia, hypertension,
and diabetes, were significantly pronounced in case patients (Table 1).
View this table:
[in a new window]
Table 1. Characteristics of Case Patients and Control
Subjects . The allele frequencies
in all subjects were obeyed according to Hardy-Weinberg's law. The T
allele frequencies of C242T polymorphism in control subjects
and case patients were 0.13 and 0.08, respectively, and the prevalence
of the TC+TT genotype was significantly more frequent in
control subjects than in CAD patients. Conversely, the allele
frequencies of A640G polymorphism were not different between
control subjects and case patients. The odds ratio of the TC+TT versus
the CC genotype of the C242T polymorphism between case
patients and control subjects was 0.49 (95% CI, 0.28 to 0.87)
(P=.015). The association of this polymorphism with CAD
was statistically significant and independent of the A640G
polymorphism and other risk factors when subjected to logistic
regression analysis (Table 2B).
View this table:
[in a new window]
Table 2. Polymorphism of the NADH/NADPH Oxidase
p22 phox Gene
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The present study is the first clinical investigation on the
significance of polymorphism of the genes related to
·O2- production
in CAD. We found that the T allele in the C242T polymorphism of
the p22 phox gene was significantly more frequent in control
subjects than in CAD patients, indicating that the mutation of the
potential heme-binding site in the p22 phox gene might have
a protective effect on coronary risk.
Selected Abbreviations and Acronyms
CAD
=
coronary artery disease
·O2-
=
superoxide
RFLP
=
restriction fragment length polymorphism
VSMC
=
vascular smooth muscle cell
Acknowledgments
We are grateful to Kiyoko Matsui for her skillful technical
assistance.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Alexander RW. Hypertension and the
pathogenesis of atherosclerosis: oxidative stress and
the mediation of arterial inflammatory response: a new
perspective. Hypertension. 1995;25:155–161.
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