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From the Institute for Medical Biochemistry (H.S., A.G., G.M.K.), the
Department of Neurology (R.S., K.N., N.W., H.-P.H.), and the Department of
Internal Medicine (M.S.), Karl-Franz University, Graz, Austria.
Correspondence to Helena Schmidt, MD, Institute for Medical Biochemistry, Karl-Franz University Graz, Harrachgasse 21 A-8010 Graz, Austria. E-mail helena.schmidt{at}kfunigraz.ac.at
Methods—The paraoxonase genotypes at positions 54 and 191
of 316 randomly selected individuals aged 44 to 75 years were
determined by polymerase chain reaction–based restriction enzyme
digestion. Carotid atherosclerosis was assessed by
color-coded Duplex scanning and was graded on a 5-point scale ranging
from 0 (normal) to 5 (complete luminal obstruction).
Results—The LL, LM, and MM genotypes at position 54 were
noted in 137 (43.4%), 132 (41.8%), and 47 (14.9%) subjects; the AA,
AB, and BB genotypes at position 191 occurred in 172 (54.4%),
124 (39.2%), and 20 (6.3%) individuals. The LL genotype was
significantly associated with the presence and severity of carotid
disease (P=0.022), whereas the 191 polymorphism had
no effect. Logistic regression analysis with age and sex forced
into the model demonstrated plasma fibrinogen (odds ratio [OR], 1.005
per mg/dL), LDL cholesterol (OR, 1.01 per mg/dL),
cardiac disease (OR, 1.75), and the paraoxonase LL genotype to
be significant predictors of carotid atherosclerosis.
The ORs for the associations with age and sex were 1.09
(P=0.0003) and 1.66 (P=0.052) per
year.
Conclusions—These data suggest that the paraoxonase LL
genotype may represent a genetic risk factor for
carotid atherosclerosis.
The human serum paraoxonase is a 43- to 45-kDa protein. Its gene is
located at q21 to q22 on the long arm of chromosome
7.9 The amino acid sequence of paraoxonase is
highly conserved among animal species, suggesting an important
metabolic role for this enzyme.10 The
ability of paraoxonase to detoxify organophosphorous compounds has been
known for years. Its activity was determined earlier by the use of
paraoxon, a widely used pesticide. The
physiological substrate of paraoxonase is yet
unknown. Watson et al11 reported recently that an
oxidized phospholipid may represent a potential
candidate. White populations have a triphasic
distribution of serum paraoxonase activity towards paraoxon but not to
other substrates such as phenylacetate.7 This
difference in enzyme activity is caused by an amino acid substitution
at position 191. Glutamine (A allele) is replaced by arginine (B
allele) in the high-activity isoform.9 The B
allele has been shown to be associated with coronary heart
disease.12 13 14 Another frequent polymorphism
present at position 54 involves a methionine (M allele) leucine
(L allele) interchange.9 The 2
polymorphisms are in linkage disequilibrium, with leucine at
position 54 giving rise for arginine at position
191.9 The suspected role of paraoxonase in the
protection of LDL against oxidative modification, and the positive
association found between paraoxonase genotypes and
coronary heart disease, prompted us to investigate the effect
of both 54 and 191 polymorphisms on carotid
atherosclerosis in a normal middle-aged and elderly
population.
Vascular Risk Factors
Study participants were defined as smokers if they currently smoked
>10 cigarettes a day. From current smokers and ex-smokers information
was obtained as to the daily number of tobacco products smoked and
smoking duration in years. The data on the amount of tobacco were
converted into grams of tobacco consumed during the lifetime using the
following conversion factors: 1 cigarette=1 g, 1 cheroot=3 g, 1 cigar=5
g. For measurements of hematocrit, blood was obtained from a large
antecubital vein without stasis.
The body mass index was calculated as weight (kg)/height
(m2). The regular use of estrogen replacement
therapy was recorded among all female study participants.
A lipid status including the level of triglycerides, total
cholesterol, LDL and HDL cholesterol, as well
as lipoprotein(a) [Lp(a)], apolipoprotein (apo) B, and apoA-I was
determined for each study participant. Thirty minutes after
venipuncture, the coagulated blood samples were
centrifuged at 1600g for 10 minutes, and the serum
was transferred to plastic tubes and analyzed within 4 hours.
Triglycerides and total cholesterol were
enzymatically determined using commercially available kits (Uni-Kit III
"Roche" and MA-Kit 100 "Roche," Hoffman-La-Roche). HDL
cholesterol was measured by the use of the TDx REA
Cholesterol assay (Abbott). LDL cholesterol was
calculated by the equation of Friedewald. The Lp(a) concentration was
determined by the electroimmunodiffusion method using a reagent kit
containing monospecific anti-Lp(a) antiserum and Rapidophor M3
equipment (Immuno AG). The levels of apoB and apoA-I were assessed by
an immunoturbidometric method using polyclonal antibodies and a laser
nephelometer (Behringwerke AG).
The plasma fibrinogen concentration was measured according to the
Clauss method19 using the prescription and
reagents of Behringwerke AG.
Isolation of DNA and Genotype Analysis
Genotyping of the Leu-Met54 polymorphism was done by
polymerase chain reaction (PCR) amplification of a 170-bp-long fragment
using the primers described by Humbert et al.9
The PCR products are cleaved by NlaIII in the presence
of BSA at 37°C for 3 hours. The digested products are
analyzed on a 15% polyacrylamide gel, stained with
ethidium bromide, and examined under UV transillumination. The L
allele corresponded to the nondigested 170-bp-long fragment, while
the M allele corresponded to a 126-bp and a 44-bp fragment. A
similar protocol was used for genotyping the Gln-Arg-191
polymorphism using the primers described by Humbert et
al.9
Carotid Duplex Scanning
Statistical Analysis
Table 2
Sonographic scores among the 3 genotypes for both
polymorphisms are shown in Table 3
The Gln-Arg-191 polymorphism did not modulate the effect of the LL
genotype on carotid disease because atherosclerotic changes
were present in almost identical frequency in 74 (62.7%) subjects
in the LL/AA group and in 12 (63.2%) individuals in the LL/BB
group.
The relative contribution of the paraoxonase LL genotype to the
presence of carotid atherosclerosis was determined by
stepwise forward logistic regression analysis (Table 4
We failed to detect a significant association between the Gln-Arg-191
polymorphism and carotid disease, although atherosclerotic lesions
were more common in BB than in AB or AA carriers. We found that
individuals with the combination of the LL/BB genotypes had
frequency of atherosclerosis virtually identical to
that of those with combined LL/AA genotypes. This indicates
that the Gln-Arg-191 polymorphism has no effect on carotid
atherosclerosis per se and does not modulate the effect
of the L allele on atherosclerosis. The Gln-Arg-191
polymorphism was defined as the molecular basis for the difference
of paraoxonase activity observed against the artificial substrate,
paraoxon.9 It was frequently reported to be
associated with coronary heart
disease.12 13 14 Blatter-Garin et
al24 reported for the first time that in whites
the Leu-Met54 polymorphism was significantly and independently of
the polymorphism at position 191 associated with the concentration
and activity of paraoxonase. These authors also found that the LL
genotype predicted coronary heart
disease.24 Similarly to our results, the effect
was present in LL homozygotes only, indicating a recessive effect
of the L allele. Sanghera et al25
investigated the effect of the Gln-Arg-191 polymorphism on
coronary heart disease in the genetically distinct populations
of Chinese and Asian Indians and found a race-specific association with
coronary heart disease with the B allele only in Indian
cohort. The inconsistency of associations in different
populations strongly indicates that the polymorphism at position
191 is not causally related to atherosclerosis but is
rather a marker for a functional sequence variant in its vicinity.
Whether the Leu-Met54 polymorphism represents this
functional variant is unclear and cannot be elucidated by association
studies.
Several recent publications support the role of paraoxonase in
atherosclerosis. Paraoxonase is tightly associated with
antiatherogenic HDL. According to recent studies, only certain
subfractions of HDL are able to reduce the risk of
atherosclerosis. Results from apoA-I and apoA-II
transgenic (tg) mice underline this
assumption.26 27 28 ApoA-II tg mice are prone to
atherosclerosis while apoA-I tg mice were found to be
protected against it, even though both had significantly increased HDL
levels compared with control mice.29 HDL isolated
from the apoA-I tg mice had been shown to protect against the
accumulation of lipid peroxides on LDL, whereas HDL from apoA-II tg
mice had no similar effect. The loss of ability of the apoA-II HDL to
protect against LDL oxidation was associated with a decreased level of
paraoxonase. Substitution of apoA-II HDL with paraoxonase restored its
antioxidative ability.29 Paraoxonase is
associated with a certain subfraction of HDL also containing apoA-I and
apoJ.7 This HDL subfraction seems to play a
central role in the antioxidative effect of
HDL.30 Navab et al31 have
found that in HepG2 cell culture, minimally oxidized LDL induces an
increase in the apoJ/paraoxonase ratio due to altered transcriptional
rates. They also reported an increase in the apoJ/paraoxonase ratio in
different animal models of atherosclerosis on
atherogenic diet, such as in mice prone to
atherosclerosis, in apoE knockout mice, and in LDL
receptor knockout mice. Interestingly, normolipidemic patients with
coronary artery disease also had a significantly higher
apoJ/paraoxonase ratio than normolipidemic
controls.30
Moreover, paraoxonase immunoreactivity was found in atherosclerotic
lesions, and the intensity of immunoreactivity in the
arterial walls increased with the progression of
atherosclerosis.32 Recently, it
was described by the same authors that paraoxonase is present in
the interstitial fluid in an enzymatically active
form.33 This is in line with the hypothesis that
paraoxonase prevents the accumulation of lipid peroxides on LDL, a
process that has to take place in the subendothelial
space. If paraoxonase is involved in atherogenesis by its ability to
prevent accumulation of lipid peroxides on LDL, and if the association
between the L allele and carotid atherosclerosis is
causal, then one would expect that the L isoform is less effective in
preventing the oxidative modification of LDL than the M isoform. A
recent report from Mackness et al34 supports this
hypothesis. These authors investigated the antioxidative effect of HDL
isolated from individuals carrying the AA, AB, or BB genotype
on Cu2+-induced oxidation of LDL. They found that
HDL from BB subjects completely lost its ability to prevent LDL
oxidation within 6 hours, whereas HDL from AB or AA individuals still
kept 23% and 40% of its original protective activity, respectively.
Given the strong linkage disequilibrium between the B and the L
allele, it is most likely that the L isoform has similar effects.
In line with this suggestion, another recent work from Mackness et
al35 showed that HDL from subjects with the MM/AA
genotype most effectively protects oxidative modification,
whereas HDL from subjects with the LL/BB genotype has the
lowest antioxidative potential.
Several groups reported that the genotype at the paraoxonase
locus influences the concentration and/or activity of serum
paraoxonase, which partly maybe due to an altered expression of the
paraoxonase gene.36 A weakness of our study is
that due to the lack of frozen serum from our participants, we were not
able to measure paraoxonase concentration and activity to test the
effect of genotype on these parameters in our
collective.
Our study is an allelic association study and cannot provide an
explanation for the mechanism(s) of the paraoxonase genotypes
leading to carotid disease. It might be that there exists a true causal
relationship between leucine at position 54 in the paraoxonase enzyme
and atherosclerosis; however, the possibility that the
association is due to a linkage disequilibrium between the L allele
and another functional allele in its neighborhood cannot be
excluded. The PON1 gene is a member of a multigene family including
PON2 and PON3 located at the same locus on chromosome
7.37 Recently, Hegele et
al38 and Sanghera et al39
described 2 polymorphisms present in the PON2 gene with
possible clinical relevance. However, function of the PON2 gene
product is still unknown, making the estimation of the importance
of these findings difficult.
In summary, this is the first report on a positive association between
the paraoxonase LL genotype and carotid
atherosclerosis. Independent of other vascular risk
factors, homozygosity for the L allele was associated with a
1.91-fold increased risk for carotid disease. If our results can be
confirmed in other ethnic groups, the Leu-Met54 variant, which can be
easily determined by conventional DNA technology, may be considered to
be included in the early risk assessment for stroke.
Received May 22, 1998;
revision received July 15, 1998;
accepted July 21, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Paraoxonase PON1 Polymorphism Leu-Met54 Is Associated With Carotid Atherosclerosis
Results of the Austrian Stroke Prevention Study
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Genetic
polymorphism at the paraoxonase locus is associated with serum
concentration and activity of paraoxonase and with increased risk for
coronary heart disease. Two frequent polymorphisms
present at the paraoxonase gene are the methionine (M allele)
leucine (L allele) interchange at position 54 and the arginine (B
allele) glutamine (A allele) interchange at position 191. This
is the first study to determine the effect of these polymorphisms
on carotid atherosclerosis.
Key Words: atherosclerosis • carotid arteries • genetics • paraoxonase
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Carotid atherosclerosis is considered to
be a major cause of ischemic stroke.1 In
recent years, oxidative stress has been demonstrated to play an
important role in the pathogenesis of
atherosclerosis.2 Low-density
lipoprotein (LDL) seems to be the major target of oxidative
modification, making it particularly
atherogenic.3 4 Identification of factors
protecting against oxidative modification of LDL are therefore of major
interest. High-density lipoprotein (HDL) has been shown to have
antioxidative potential; however, the mechanism(s) of its action is not
known.5 One mechanism might be the enzymatic
removal of lipid peroxides accumulating on the LDL particle by enzymes
present on HDL.6 Paraoxonase is tightly
associated with HDL and has been shown to reduce the accumulation of
lipid oxidation products on LDL.7 8
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Study Population
Individuals aged 44 to 75 years and stratified by sex and 5-year
age groups were randomly selected from the official register of
residents of the city of Graz, Austria. They received a written
invitation to participate in the Austrian Stroke Prevention Study
(ASPS), a single-center prospective follow-up study in our community.
The study has been approved by the Medical Ethics Committee of the
Karl-Franzens University of Graz. Written informed consent was obtained
from all study participants. The rationale and design of the ASPS have
been previously described.15 Briefly, the
objective of the study is to examine the frequency of cerebrovascular
risk factors and their effects on carotid
atherosclerosis, as well as on cerebral morphology and
function, in the normal elderly. The inclusion criteria for the study
were no history of neuropsychiatric disease and a normal neurological
examination. From a total of 8193 individuals invited between September
1991 and March 1994, a sample of 2794 subjects agreed to participate,
with 1998 individuals fulfilling the inclusion criteria. All study
participants underwent a structured clinical interview, a physical and
neurological examination, 3 blood pressure readings, ECG, and
echocardiography, as well as laboratory testing
including blood cell count and a complete blood chemistry panel. Every
fourth study participant was then invited to enter phase II of the
ASPS, which included Doppler sonography, MRI, SPECT, and
neuropsychological testing. Since 1993, we started to establish a gene
bank in all phase II attendees. The present study cohort consists
of those 316 individuals who underwent both carotid duplex scanning and
assessment of the paraoxonase polymorphisms. There were 158 women
and 158 men. The mean age of this cohort was 60.0±6.1 years.
Diagnosis of vascular risk factors relied on the individuals'
histories and appropriate laboratory findings. Arterial
hypertension was considered present if a subject had a history of
arterial hypertension with repeated
systolic/diastolic blood pressure readings
>160/95 mm Hg or if the readings at examination exceeded this
limit. Diabetes mellitus was coded present if a subject was treated
for diabetes at the time of the examination or if the fasting blood
glucose level at examination exceeded 140 mg/dL. Cardiac disease was
assumed to be present if there was evidence of cardiac
abnormalities known to be a source for cerebral
embolism,16 evidence of coronary heart
disease according to the Rose questionnaire17 or
appropriate ECG findings18 (Minnesota codes I: 1
to 3; IV: 1 to 3; or V: 1 to 2), or if an individual presented
with signs of left ventricular hypertrophy on
echocardiogram or ECG (Minnesota codes III: 1; or IV: 1 to 3).
High-molecular-weight DNA was extracted from
peripheral whole blood using Qiagen genomic tips (Qiagen
Inc) according to the protocol of the manufacturers.
Color-coded equipment (Diasonics, VingMed CFM 750) was used to
determine atherosclerotic vessel wall abnormalities of the carotid
arteries. All B-mode and Doppler data were transferred to a
Macintosh personal computer for postprocessing and storage on optical
disks. The imaging protocol involved scanning of both common and
internal carotid arteries in multiple longitudinal and transverse
planes and has been previously described.20 21
The examinations were done by one experienced physician. Image quality
was assessed and graded into good (common and internal carotid arteries
clearly visible and internal carotid arteries detectable over a
distance of >2 cm), fair (common and internal carotid arteries
sufficiently visible and internal carotid arteries detectable over a
distance of at least 2 cm), and poor (common and internal carotid
arteries insufficiently visible or internal carotid arteries detectable
over a distance of <2 cm). The image quality was good in 308 (97%)
and fair in 8 (3%) individuals. It was never poor. Measurements of
maximal plaque diameter were done in longitudinal planes, and the
extent of atherosclerosis was graded according to the
most severe visible changes in the common and internal carotid arteries
as 0=normal, 1=vessel wall thickening (>1 mm), 2=minimal plaque
(<2 mm), 3=moderate plaque (2 to 3 mm), 4=severe plaque
(>3 mm), and 5=lumen completely obstructed. Assessment of the
intrarater reliability of this score was done in 50 randomly selected
subjects and yielded a 
value of 0.83.
We used the Statistical Package for Social Sciences (SPSS/PC+)
for data analysis. Categorical variables among the
paraoxonase genotypes were compared by
2 test. Assumption of normal distribution for
continuous variables was tested by Lilliefors statistics. Normally
distributed continuous variables were compared by 1-way ANOVA,
whereas the Kruskal-Wallis test was used for comparison of nonnormally
distributed variables. ANCOVA and logistic
multivariate regression analysis were used to
adjust for possible confounding in the comparison of risk factors among
paraoxonase genotypes. Allele frequencies were calculated
by the gene counting method, and Hardy-Weinberg equilibrium was
assessed by 2 test. To test the differences in
sonographic score among the 3 genotypes at both polymorphic
sites, Kruskal-Wallis 1-way ANOVA was used. To assess the relative
contribution of the paraoxonase genotypes on the presence of
carotid atherosclerosis, we used multiple logistic
regression analysis. The sonographic score was dichotomized
into normal (grade 0) or abnormal (grade 1 through 5). Vessel wall
thickening (grade 1) was considered to be abnormal because it has been
shown to represent an early stage of
atherosclerosis and to be associated with an increased
risk for future stroke.22 23 Forward selection
stepwise regression analysis with age and sex forced into the
model assessed independent predictors of carotid disease. At each step,
each variable not in the model was assessed as to its contribution
to the model, and the most significant variable was added to the
model. This process continued until no variable not in the model
made a significant (P<0.05) contribution. Odds ratios (ORs)
and 95% confidence intervals (CIs) were calculated from the ß
coefficients and their standard errors.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The genotypes LL, LM, and MM were noted in 137 (43.4%),
132 (41.8%), and 47 (14.9%) study participants. The AA, AB, and BB
genotypes occurred in 172 (54.4%), 124 (39.2%), and 20
(6.3%) study participants, respectively. The genotypes of both
polymorphisms were in Hardy-Weinberg equilibrium. As shown in Table 1
, there was a moderate association
between the 2 polymorphisms, with arginine at position 191 being
with 1 exception always concurrent with leucine at position
54.
View this table:
[in a new window]
Table 1. Distribution of Paraoxonase Genotypes
Defined by Amino Acid Substitution at Positions 54 and 191 compares demographic
variables and risk factors among the LL, LM, and MM
genotype subsets. There was no significant difference between
groups, with the exception of lower glucose levels and less frequent
cardiac disease in those with the LM genotype. The significant
difference in blood glucose level remained unchanged after adjustment
for age, sex, and cardiac disease (P=0.03) but was no longer
present after correction for use of antidiabetic treatment
(P=0.26). Correction for use of lipid-lowering treatment did
not materially change the results of comparisons of blood lipids
between the 3 investigational subsets. The between-group difference for
cardiac disease remained significant after adjustment for age, sex, and
glucose level (P=0.04). There was no significant difference
among the AA, AB, and BB genotype subsets when the demographic
variables and risk factors listed in Table 2 were compared (data
not shown).
View this table:
[in a new window]
Table 2. Demographics and Risk Factors Among Paraoxonase
Leu-Met54 Genotypes .
Overall, there were 63 (47.7%) subjects with the LM genotype
and 23 (48.9%) subjects with the MM genotype, but 86 (62.7%)
subjects with the LL genotype showed an abnormal sonographic
score. Subjects homozygous for the L allele had higher grades of
carotid abnormalities than subjects with either the LM or MM
genotype (P=0.022). Logistic regression
analysis yielded an unadjusted OR of 1.86 (95% CI, 1.18 to
2.94; P=0.007) for abnormal sonographic findings in the LL
genotype relative to the other 2 genotypes. The OR
after adjustment for age and sex was 1.98 (95% CI, 1.23 to 3.20;
P=0.005) and 1.88 (95% CI, 1.16 to 3.05; P=0.01)
when adjusting for age, sex, fasting glucose level, and cardiac
disease. Evaluation of the effect of the Gln-Arg-191 polymorphism
on carotid atherosclerosis demonstrated that subjects
with the BB genotype had the highest prevalence of carotid
abnormalities. This difference between the genotypes did not
reach statistical significance (P=0.481).
View this table:
[in a new window]
Table 3. Paraoxonase Genotypes and Duplex Score ). Age and sex was forced in the model.
This analysis demonstrated the LL genotype to be
significantly and independently associated with carotid
atherosclerosis (P=0.014). Plasma fibrinogen
entered first (OR, 1.005 per mg/dL), LDL cholesterol second
(OR, 1.012 per mg/dL), the LL genotype third (OR, 1.907), and
cardiac disease fourth (OR, 1.748). No other variables such as
total cholesterol, HDL cholesterol,
triglycerides, hypertension, diabetes mellitus, smoking,
hematocrit, or body mass index were entered into the model. The ORs for
the associations with age and sex were 1.09 (P=0.0003) and
1.66 (P=0.05) per year, respectively.
View this table:
[in a new window]
Table 4. Final Logistic Regression Analysis:
Predictors of Carotid Atherosclerosis
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Our data suggest that the paraoxonase LL genotype at
position 54 is a significant and independent predictor of carotid
atherosclerosis in a middle-aged and elderly
population. Homozygosity for the L allele is associated with higher
frequency and severity of carotid abnormalities, whereas heterozygosity
for this allele results in no risk increase.
Acknowledgments
This project was partly supported by the Austrian Research
Foundation Project P11691, SFB702 (Dr Kostner) and by the Franz
Lanyar Stiftung of the Karl-Franz University (Dr H. Schmidt), Graz,
Austria. The excellent technical assistance of Johann Semmler is
appreciated.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
T) is associated
with carotid atherosclerosis: results of the Austrian
Stroke Prevention Study. Arterioscler Thromb Vasc Biol. 1998;18:487–492.
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G. P. Jarvik, L. S. Rozek, V. H. Brophy, T. S. Hatsukami, R. J. Richter, G. D. Schellenberg, and C. E. Furlong Paraoxonase (PON1) Phenotype Is a Better Predictor of Vascular Disease Than Is PON1192 or PON155 Genotype Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20(11): 2441 - 2447. [Abstract] [Full Text] [PDF]
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R. Schmidt, H. Schmidt, F. Fazekas, P. Kapeller, G. Roob, A. Lechner, G. M. Kostner, and H.-P. Hartung MRI Cerebral White Matter Lesions and Paraoxonase PON1 Polymorphisms : Three-Year Follow-Up of the Austrian Stroke Prevention Study Arterioscler. Thromb. Vasc. Biol., July 1, 2000; 20(7): 1811 - 1816. [Abstract] [Full Text] [PDF]
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