(Circulation. 1998;98:1881-1885.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Association of a G994
T Missense Mutation in the Plasma Platelet-Activating Factor Acetylhydrolase Gene With Genetic Susceptibility to Nonfamilial Dilated Cardiomyopathy in Japanese
From the First Department of Internal Medicine (S.I.) and Department of Clinical Laboratory Medicine (M.Y.), Nagoya University School of Medicine, and Department of Geriatric Research (Y.Y.), National Institute for Longevity Sciences, Obu, Aichi, Japan.
Correspondence to Mitsuhiro Yokota, MD, PhD, Department of Clinical Laboratory Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
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Abstract |
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Background—Although several genes or genetic loci that are responsible for or confer susceptibility to familial dilated cardiomyopathy (DCM) have been identified, genetic defects that underlie nonfamilial DCM remain to be characterized. Mice lacking manganese superoxide dismutase exhibit DCM, suggesting that impairment of the defense mechanisms against oxidative stress is an important susceptibility factor for DCM. Plasma platelet-activating factor (PAF) acetylhydrolase also acts as a key defense against oxidative stress by hydrolyzing PAF and oxidized phospholipids. Thus, abnormalities in the activity of this enzyme may result in predisposition to myocardial damage.
Methods and Results—The possible association of a
G994 (M allele)T (m
allele) missense mutation in the plasma PAF acetylhydrolase
gene with genetic susceptibility to nonfamilial DCM has now been
investigated in 122 Japanese individuals with this condition and 226
healthy control subjects. PAF acetylhydrolase activity in plasma was
significantly associated with plasma PAF acetylhydrolase
genotype in both DCM patients and healthy control subjects. The
frequency of the mutant m allele was significantly
higher in DCM patients than in control subjects. Left
ventricular mass (LVM) and the LVM index in DCM patients
with Mm or mm genotypes were
significantly greater than those in patients with the MM
genotype.
Conclusions—The G994T mutation in the plasma PAF
acetylhydrolase gene is associated with nonfamilial DCM in Japanese
subjects. Although the mutation is unlikely to be a causative factor,
it may contribute to genetic susceptibility to or progression of
nonfamilial DCM.
Key Words: genes • platelets • cardiomyopathy
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and impaired systolic contraction and manifests clinically by pump failure or sudden death. Genetic loci responsible for familial DCM have been mapped to chromosomes 1p1-1q1,1 1q32,2 3p22-p25,3 9q13-q22,4 and 10q21-q23.5 In other families with phenotypes similar to DCM but with a different pattern of genetic transmission, 2 X-linked responsible genes were mapped to Xq286 and Xp21.7 In the latter instance, a defect in the dystrophin gene appears to contribute to susceptibility to DCM.8 Although 80% of DCM cases are not inherited,9 the potential contributions of genetic defects to nonfamilial DCM have not been investigated extensively.
Tissue damage mediated by oxygen-derived free radicals has been implicated in a variety of pathological conditions, including ischemia-reperfusion injury of the heart, amyotrophic lateral sclerosis, and acute respiratory distress syndrome.10 11 Mice lacking the activity of manganese superoxide dismutase (MnSOD), which is important in the control of dioxygen toxicity in mitochondria in instances of extreme oxidative load, exhibit an abnormality of the myocardium identical to the pathological changes characteristic of DCM.12 13 This observation suggests that defects in the defense mechanisms against oxidative stress may contribute to genetic susceptibility to DCM.
Oxidative stress induces the expression of the proinflammatory phospholipid platelet-activating factor (PAF) in endothelial cells and macrophages.14 PAF increases vascular permeability and exerts marked hemodynamic effects. Intravenous injection of PAF induces hypotension, increases systolic vascular resistance, and reduces the cardiac index in dogs.15 PAF may also act as a secondary mediator of the effects of oxygen radicals in the heart.16 A strongly oxidizing environment induces fragmentation of the polyunsaturated fatty acids of cell membrane phospholipids.17 The resulting oxidized phospholipids are structurally similar to PAF and mimic its biological actions.18 The biological effects of both PAF and oxidized phospholipids are abolished by hydrolysis of the sn-2 residue, a reaction catalyzed by PAF acetylhydrolase.19 20 21 Given that PAF acetylhydrolase constitutes a key defense against oxidative stress, abnormalities in the activity of this enzyme may result in predisposition to myocardial damage.
The plasma PAF acetylhydrolase gene is located on chromosome 6p12-p21.1
and exhibits a GT mutation at nucleotide position 994 in
exon 9, which encodes the catalytic domain.22
This nucleotide change results in a ValPhe substitution
at amino acid 279 of the mature protein and a consequent loss of
catalytic activity. However, the role of reduced or no enzyme activity
caused by this mutation in the genetic susceptibility to DCM has not
been determined. We have now investigated the possible association of
the G994T missense mutation in the plasma PAF
acetylhydrolase gene with nonfamilial DCM in Japanese subjects.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
The study population consisted of 348 unrelated Japanese subjects (122 patients with nonfamilial DCM and 226 healthy individuals) who had visited 14 participating hospitals. Informed consent was obtained from all subjects. The diagnosis of DCM was based on patient history, physical examination, ECG, chest radiograph, echocardiography, left ventriculography, and coronary angiography. All patients were free of hypertension, ischemic heart disease, valvular heart disease, congenital malformations of the heart or vessels, and intrinsic pulmonary, renal, or metabolic diseases. Endomyocardial biopsies were obtained to rule out secondary cardiomyopathies caused by viral or other infectious myocarditis, sarcoidosis, amyloidosis, hemochromatosis, or other metabolic heart diseases. Patients with secondary DCM were excluded from the study. Healthy individuals were selected as a normal control group; they had visited the hospitals for an annual medical checkup and did not exhibit any serious disorders. The age, sex, body mass index, and systolic and diastolic blood pressures did not differ significantly between the 2 groups.
Plasma PAF Acetylhydrolase Activity
Venous blood was collected into tubes containing EDTA (disodium
salt; final concentration, 50 mmol/L) and centrifuged at
1600g for 15 minutes at 4°C. Plasma samples were stored at
-30°C. PAF acetylhydrolase activity in plasma was measured according
to the method of Stafforini et al.19
Genotype Analysis of Plasma PAF
Acetylhydrolase Gene
Venous blood (7 mL) was collected into tubes containing EDTA (as
above), and after separation of leukocytes, genomic DNA was isolated.
Plasma PAF acetylhydrolase genotype was determined by
allele-specific polymerase chain reaction (PCR) with 1 sense primer
(5'-CTATAAATTTATATCATGCTT-3') and 2 antisense primers
(5'-TCACTAAGAGTCTGAATAAC-3' and
5'-TCACTAAGAGT-CTGAATAAA-3').22 Reactions were
performed in a total volume of 50 µL containing 0.5 µg of genomic
DNA, 20 pmol of each primer, 0.2 mmol/L of each dNTP, 1 U of
Taq DNA polymerase, 50 mmol/L KCl, 1.5 mmol/L
MgCl2, and 10 mmol/L Tris-HCl (pH 8.3). The
thermocycling procedure consisted of initial denaturation at 94°C for
5 minutes; 5 cycles of denaturation at 94°C for 1 minute, annealing
at 56°C for 1 minute, and extension at 72°C for 1 minute; 30 cycles
of 94°C for 30 seconds, 52°C for 30 seconds, and 72°C for 30
seconds; and a final extension at 72°C for 5 minutes. The PCR
products were analyzed by electrophoresis on a 2% agarose
gel and visualized by ethidium bromide staining. Because the
G994T transversion produces a new restriction
site for Mae II, plasma PAF acetylhydrolase
genotypes were designated MM (normal), Mm
(heterozygous), and mm (homozygous deficient).
Echocardiographic Examination
Patients with DCM were subjected to
echocardiographic examination. The left
ventricular end-diastolic dimension (LVEDD) and
end-systolic dimension (LVESD), as well as the
end-diastolic thickness of the interventricular
septum and the left ventricular posterior wall, were
determined by M-mode echocardiography. The left
ventricular ejection fraction was calculated by the method
of Teichholz et al.23 Left
ventricular mass (LVM) was calculated by the method of
Devereux and Reichek,24 and the LVM index (LVMI)
was calculated by dividing LVM by body surface area.
Statistical Analysis
Data are presented as mean±SD. Age, body mass index,
and systolic and diastolic blood pressures were
compared between healthy control subjects and DCM patients by
Student's nonpaired t test or the Mann-Whitney U
test. Comparison of data among PAF acetylhydrolase genotypes
was performed by 1-way ANOVA and Scheffé's multiple-range test.
Echocardiographic data were compared by Student's
nonpaired t test or the Mann-Whitney U test.
Allele frequency was estimated by gene counting and
2 analysis. Hardy-Weinberg equilibrium
was also confirmed by 2 test. A value of
P<0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Allele-specific PCR analysis accurately detected the G994 (M allele)
T (m
allele) mutation in the plasma PAF acetylhydrolase gene. Among 226
control subjects, the frequencies of the MM, Mm,
and mm genotypes were 76.5%, 21.7%, and 1.8%,
respectively (Table 1
). The distribution
of the genotypes was in Hardy-Weinberg equilibrium. The
frequency of the m allele was significantly higher in
DCM patients than in control subjects (P=0.003; odds ratio,
1.9).
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The relation between plasma PAF acetylhydrolase genotype and
enzyme activity in plasma was analyzed in control subjects and
DCM patients (Table 2). The
PAF acetylhydrolase activity in plasma was significantly associated
with genotype in both control subjects and DCM patients. Enzyme
activity in individuals with the MM genotype
significantly exceeded that in individuals with Mm or
mm genotypes. No significant activity was detected
in individuals with the mm genotype. No difference
in plasma PAF acetylhydrolase activity was detected between control
subjects and DCM patients of the same genotype.
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The relation between PAF acetylhydrolase genotype and left
ventricular function determined by
echocardiography was investigated in the patients
with DCM (Table 3). The
LVEDD, LVESD, LVM, and LVMI in DCM patients with Mm or
mm genotypes were significantly greater than those
in patients with the MM genotype.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although the potential contributions of genetic defects to nonfamilial DCM remain to be characterized, the pathogenesis of this condition is thought to be multifactorial, involving the interaction of genetic and environmental influences. The myocardial response to stimuli may be modulated by a variety of genes that interact with each other, and the final phenotype is probably the consequence of the interaction of the responsible genes with the genetic background and the environment.25 We have now detected an association of the G994
T mutation in the
plasma PAF acetylhydrolase gene with the prevalence of nonfamilial DCM
in Japanese. Because the plasma activity of the enzyme is determined by
the genotype, low or no activity may be an important factor in
genetic susceptibility to nonfamilial DCM. Kimball et
al26 showed that LVM remained increased in
symptomatic childhood DCM patients at follow-up, suggesting
that LVM may be a predictor of disease progression. In a prospective
study of DCM patients followed up for up to 7 years, Douglas et
al27 demonstrated that reduced survival was
associated with greater LVEDD and LVESD. Our results show that LVM and
LVMI, as well as LVEDD and LVESD, were significantly greater in DCM
patients with Mm or mm genotypes than in
patients with the MM genotype. Thus, it is possible
that this mutation of the plasma PAF acetylhydrolase gene may affect
the progression of nonfamilial DCM. One of the key processes in the genesis or progression of DCM may be oxidative damage to the myocardium. Oxygen-derived free radicals have been implicated in the pathogenesis of ischemic and postischemic reperfusion injury in the heart.10 Free radical–generating systems impair the function of several cardiac structures and proteins in vitro, including the sarcoplasmic reticulum, Na+-K+ pump, myofibrillar ATPase, and mitochondria.28 The heart is highly susceptible to free radical injury because it contains smaller amounts of detoxifying substances, including glutathione, catalase, and SOD, than do metabolic organs such as the liver or kidney.29 Doxorubicin, an antineoplastic agent that is also cardiotoxic, stimulates the production of free radicals in both isolated cardiac sarcoplasmic reticulum and mitochondria.30 Doxorubicin tips the balance in favor of oxidants by both increasing the formation of oxygen free radicals and reducing the amount of endogenous antioxidants. Although several mechanisms have been suggested to explain the pathogenesis of doxorubicin-induced cardiomyopathy, free radical–induced oxidative stress appears to play a pivotal role.31 In addition, oxidative damage is responsible for the observed high mutation rate of mitochondrial DNA,32 which may also be relevant to the molecular mechanisms of cardiomyopathy. Furthermore, MnSOD-deficient mice have enlarged hearts with a dilated left ventricular cavity and reduced left ventricular wall thickness, defects that resemble the pathological changes characteristic of DCM.12 13 Thus, impairment of the defense mechanisms against oxidative stress may be an important susceptibility factor for DCM.
PAF is produced by endothelial cells in response to oxidative stress and can induce macrophages to produce superoxide anions, resulting in an amplification of the pathogenic effects of oxidative stress.14 PAF also acts as a secondary mediator of the effects of oxygen radicals in the heart.16 PAF acetylhydrolase degrades PAF to biologically inactive lyso-PAF, suggesting that this enzyme protects against PAF-mediated pathological events. This idea is supported by the observation that recombinant plasma PAF acetylhydrolase markedly inhibits PAF-induced inflammation in rats.33 Marked oxidative stress also induces fragmentation of polyunsaturated fatty acids of cell-membrane phospholipids, which results in the production of proinflammatory oxidized phospholipids.17 PAF acetylhydrolase may protect the myocardial cell membrane from oxidative damage by hydrolyzing oxidatively fragmented fatty acyl residues at the sn-2 position of phospholipids.20 21 Given that the cardiomyocytes possess a specific receptor for PAF,34 PAF and oxidized phospholipids may act directly on the myocardium through this receptor.18 The fact that PAF acetylhydrolase degrades PAF and oxidized phospholipids to biologically inactive molecules thus suggests that it may protect the myocardium against inflammatory events mediated by these phospholipids. PAF acetylhydrolase may therefore play an important role in the mechanism of defense against oxidative damage in the myocardium.
The plasma PAF acetylhydrolase gene is located on chromosome
6p12-p21.1.22 Previously identified genetic loci
responsible for familial DCM (chromosomes 1p1-1q1, 1q32, 3p22-p25,
9q13-q22, 10q21-q23, Xq28, and Xp21) are all located on different
chromosomes.1 2 3 4 5 6 7 Therefore, there is so far no
evidence that the plasma PAF acetylhydrolase gene is in close proximity
to a gene responsible for DCM. However, it is possible that the
G994T mutation in the PAF acetylhydrolase gene
is a genetic marker for a nearby unknown gene that is responsible for
nonfamilial DCM. Even if this is the case, the mutation in the plasma
PAF acetylhydrolase gene makes a valuable contribution because it
identifies a locus that regulates the severity of the disorder. It is
unlikely that the mutation in the PAF acetylhydrolase gene is a
causative factor of nonfamilial DCM because 23.5% of control subjects
possessed the mutant allele (mm genotype, 1.8%;
Mm genotype, 21.7%) and 60.7% of DCM patients had
the MM (normal) genotype. Therefore, we propose that
an excess of PAF and oxidized phospholipids that results from plasma
PAF acetylhydrolase deficiency may contribute genetic susceptibility to
or exacerbation of nonfamilial DCM.
The distribution of plasma PAF acetylhydrolase genotypes
differs among races. In >2000 samples from individuals in North
America and Europe, heterozygous or homozygous deficient subjects have
not been identified (S.M. Prescott, MD, personal communication).
Recently, the G994T mutation in the plasma PAF
acetylhydrolase gene has been associated with thrombotic and
atherosclerotic diseases in Japan.35 36 Hiramoto
et al35 demonstrated an association of this
mutation with stroke in Hirosaki, a northern area of Japan. We have
also demonstrated that this mutation is an independent risk factor for
myocardial infarction in Japanese men, especially in low-risk
individuals.36 These clinical observations
suggest that PAF and oxidized phospholipids also play important roles
in the pathology of thrombosis and atherosclerosis and
that plasma PAF acetylhydrolase may serve as a defense mechanism in
such disorders.
In conclusion, we have demonstrated an association of the
G994T mutation of the plasma PAF
acetylhydrolase gene with nonfamilial DCM in Japanese. In addition, LVM
and LVMI determined by echocardiography in DCM
patients differed significantly among PAF acetylhydrolase
genotypes. Our results indicate that, although the
G994T mutation in the plasma PAF
acetylhydrolase gene is unlikely to be a causative factor, it may
affect defense mechanisms against oxidative stress and contribute to
genetic susceptibility to or progression of nonfamilial DCM in
Japanese.
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Acknowledgments |
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We thank T. Matsuura for technical assistance and physicians at the 14 participating hospitals for their contributions to this study.
Received March 31, 1998; accepted July 2, 1998.
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Yamada Y, Ichihara S, Fujimura T, Yokota M.
Identification of the G994T missense mutation
in exon 9 of the plasma platelet-activating factor acetylhydrolase
gene as an independent risk factor for coronary artery disease
in Japanese men. Metabolism. 1998;47:177–181.Impairment of the defense mechanisms against
oxidative stress may be an important susceptibility factor for dilated
cardiomyopathy (DCM). The association of a
G994 (M allele) T (m
allele) mutation in the plasma platelet-activating factor (PAF)
acetylhydrolase gene with nonfamilial DCM has now been investigated in
122 Japanese DCM patients and 226 healthy control subjects. PAF
acetylhydrolase activity in plasma was significantly associated with
plasma PAF acetylhydrolase genotype. The frequency of the
mutant m allele was significantly higher in DCM
patients than in healthy control subjects. Left ventricular
mass (LVM) and the LVM index in DCM patients with Mm or
mm genotypes were significantly greater than
those in patients with the MM genotype. The
G994T mutation may contribute to genetic susceptibility
to or progression of nonfamilial DCM in Japanese.[Medline]
[Order article via Infotrieve]
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