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Paraoxonase 1 gene polymorphisms in angiographically assessed coronary artery disease: evidence for gender interaction among Brazilians

TL;DR: It is shown that the 55LeuLeu Pon1 genotype increases CAD risk among female Caucasian-Brazilians, irrespective of other CAD risk factors, and that 192GlnGln PON1 homozygotes show higher triglyceride and lower HDL-cholesterol levels in male Caucasian- Brazilians.
Abstract: BACKGROUND: Paraoxonases (PON) are members of an enzyme family involved in preventing low-density lipoprotein oxidation and therefore protecting against atherosclerotic plaque formation. METHODS: We studied the Met55Leu and Gln192Arg PON1 polymorphisms in 712 patients (437 Caucasian- and 275 African-Brazilians) who underwent coronary angiography. RESULTS: Among Caucasian-Brazilians, the homozygous 55LeuLeu frequency was higher among patients with significant coronary artery disease (CAD, obstructive lesions >/=50%) than among lesion-free controls (51% vs. 30.3%; p=0.022) in females, but not in males. The Gln192Arg PON1 polymorphism was not associated with CAD, although 192GlnGln homozygotes presented lower high-density lipoprotein (HDL)-cholesterol (p=0.035) and higher triglyceride (p=0.012) levels than 192Arg allele carriers among Caucasian-Brazilian males, but not females. No other lipid-genotype association was detected. Multivariate logistic regression corrected for classic CAD risk factors shows that 55LeuLeu PON1 homozygotes were at increased CAD risk (odds ratio OR=2.852; p=0.003) and that this genotype interacted with gender in its association with CAD risk (OR=0.290; p=0.006) among Caucasian-Brazilians. CONCLUSIONS: This report shows that the 55LeuLeu PON1 genotype increases CAD risk among female Caucasian-Brazilians, irrespective of other CAD risk factors. In addition, 192GlnGln PON1 homozygotes show higher triglyceride and lower HDL-cholesterol levels in male Caucasian-Brazilians. No associations were detected among African-Brazilians.

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Summary

  • Paraoxonases (PON) are members of an enzyme family involved in preventing low-density lipoprotein oxidation and therefore protecting against atherosclerotic plaque formation, also known as Background.
  • The authors studied the Met55Leu and Gln192Arg PON1 polymorphisms in 712 patients (437 Caucasianand 275 African-Brazilians) who underwent coronary angiography.
  • Among Caucasian-Brazilians, the homozygous 55LeuLeu frequency was higher among patients with significant coronary artery disease (CAD, obstructive lesions G50%) than among lesion-free controls (51% vs. 30.3%; ps0.022) in females, but not in males, also known as Results.
  • The Gln192Arg PON1 polymorphism was not associated with CAD, although 192GlnGln homozygotes presented lower high-density lipoprotein (HDL)-cholesterol (ps0.035) and higher triglyceride (ps0.012) levels than 192Arg allele carriers among Caucasian-Brazilian males, but not females.
  • Multivariate logistic regression corrected for classic CAD risk factors shows that 55LeuLeu PON1 homozygotes were at increased CAD risk (odds ratio ORs2.852; ps0.003) and that this genotype interacted with gender in its association with CAD risk (ORs0.290; ps0.006) among Caucasian-Brazilians.
  • Caucasian-Brazilians, irrespective of other CAD risk factors.
  • In addition, 192GlnGln PON1 homozygotes show higher triglyceride and lower HDL-cholesterol levels in male Caucasian-Brazilians.

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Clin Chem Lab Med 2007;45(7):874–878 2007 by Walter de Gruyter Berlin New York. DOI 10.1515/CCLM.2007.136 2006/30
Article in press - uncorrected proof
Short Communication
Paraoxonase 1 gene polymorphisms in angiographically
assessed coronary artery disease: evidence for gender
interaction among Brazilians
Domingos L.S. Rios
1,
*, Lorenza O. D’Onofrio
2
,
Caio C.S. Cerqueira
1
, Ricardo Bonfim-Silva
1
,
Heitor G. Carvalho
3
, Ademar Santos-Filho
3
and
Bernardo Galva˜ o-Castro
2,4
1
Laborato´ rio de Gene´ tica Molecular, Universidade
Estadual do Sudoeste da Bahia (UESB), Jequie´ , BA,
Brazil
2
Centro de Pesquisas Gonc¸alo Moniz (CPqGM),
Fundaca˜ o Oswaldo Cruz (FIOCRUZ), Salvador, BA,
¸
Brazil
3
Hospital Santa Izabel, Salvador, BA, Brazil
4
Escola Bahiana de Medicina e Sau´de Pu´ blica,
Salvador, BA, Brazil
Abstract
Background: Paraoxonases (PON) are members
of an enzyme family involved in preventing low-den-
sity lipoprotein oxidation and therefore protecting
against atherosclerotic plaque formation.
Methods: We studied the Met55Leu and Gln192Arg
PON1 polymorphisms in 712 patients (437 Caucasian-
and 275 African-Brazilians) who underwent coronary
angiography.
Results: Among Caucasian-Brazilians, the homozy-
gous 55LeuLeu frequency was higher among patients
with significant coronary artery disease (CAD,
obstructive lesions G50%) than among lesion-free
controls (51% vs. 30.3%; ps0.022) in females, but not
in males. The Gln192Arg PON1 polymorphism was
not associated with CAD, although 192GlnGln homo-
zygotes presented lower high-density lipoprotein
(HDL)-cholesterol (ps0.035) and higher triglyceride
(ps0.012) levels than 192Arg allele carriers among
Caucasian-Brazilian males, but not females. No other
lipid-genotype association was detected. Multivariate
logistic regression corrected for classic CAD risk fac-
tors shows that 55LeuLeu PON1 homozygotes were
at increased CAD risk (odds ratio ORs2.852; ps0.003)
and that this genotype interacted with gender in its
association with CAD risk (ORs0.290; ps0.006)
among Caucasian-Brazilians.
Conclusions: This report shows that the 55LeuLeu
PON1 genotype increases CAD risk among female
*Corresponding author: Dr. Domingos La´ zaro S. Rios,
Laborato´ rio de Gene´ tica Molecular, Departamento de
Cieˆ ncias Biolo´ gicas-DCB, Universidade Estadual do
Sudoeste da Bahia-UESB, Avenida Jose´ Moreira Sobrinho,
s/n, Bairro-Jequiezinho, 45200-000 Jequie´ , BA, Brazil
Phone: q55-73-35289660, Fax: q55-73-35256683,
E-mail: domingosrios@hotmail.com
Caucasian-Brazilians, irrespective of other CAD risk
factors. In addition, 192GlnGln PON1 homozygotes
show higher triglyceride and lower HDL-cholesterol
levels in male Caucasian-Brazilians. No associations
were detected among African-Brazilians.
Clin Chem Lab Med 2007;45:874–8.
Keywords: African-Brazilians; coronary artery dis-
ease; paraoxonase; polymorphism.
Atherosclerosis is characterized by lipid deposition on
the inner layer of the arterial wall. Oxidized low-den-
sity lipoprotein (LDL) is the major source of lipids for
foam cell formation during atherogenesis and higher
levels of LDL are associated with high oxidative stress
conditions (1, 2). High-density lipoprotein (HDL) plays
a key role in protecting LDL from oxidation, in part
due to an esterase called paraoxonase 1 (PON1) asso-
ciated with HDL particles that can hydrolyze specific
oxidized lipids and lipoproteins (3, 4). Direct evidence
of its role in atherogenesis has come from PON1 and
apolipoprotein E (apoE) gene double-knockout mice
that presented higher lipid peroxidation levels and
developed more atherosclerosis (5, 6).
PON1 is member of the paraoxonase family that
includes three isozymes. Their genes are clustered on
chromosome 7 q 21.322.1 (7). The PON1 gene has
two widely investigated polymorphisms, Met55Leu
and Gln192Arg, which have previously been associ-
ated with LDL anti-oxidation activity (8) and coronary
artery disease (CAD) risk among Caucasians and
Asians in some but not all studies wreviewed in (9)x.
The present study aimed to investigate Met55Leu
and Gln192Arg PON1 polymorphisms and their asso-
ciations with angiographically assessed CAD and lipid
levels in Caucasian- and African-Brazilians.
A total of 712 patients (437 Caucasian- and 275 Afri-
can-Brazilians), who had undergone coronary angio-
graphy at Santa Izabel Hospital in Salvador, Bahia
state, in Northeastern Brazil, as previously described
(10), were studied. Angiography had been recom-
mended due to symptoms related to CAD, major angi-
na. Of these, 268 individuals presented no visible
coronary lesion on angiography and were taken as
controls. Among these controls, none presented acute
myocardial infarction, cerebral vascular infarction or
transient ischemic attack. The other 444 individuals
presented at least one obstructive lesion of G50% and
were taken as CAD cases, 194 of whom also present-
ed a previous history of myocardial infarction con-

Rios et al.: PON1-gender interaction on CAD risk in Brazilians 875
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Table 1 Clinical and demographic characteristics of CAD cases and controls.
Variable CAD cases Controls p
Number 444 268
Age, years 55.5
"
7.0 52.3
"
8.2 -0.001
Female/male 149/295 147/121 -0.001
Diabetes mellitus, yes/no 128/316 28/240 -0.001
Hypertension, yes/no 324/120 179/89 0.095
Current or past smoking, yes/no 254/190 117/151 0.001
Early CAD family history, yes/no 165/279 68/200 0.002
Total cholesterol, mmol/L 4.89
"
1.34 4.85
"
1.12 0.972
LDL-cholesterol, mmol/L 3.26
"
1.18 3.28
"
1.02 0.492
HDL-cholesterol, mmol/L 0.73
"
0.20 0.80
"
0.22 -0.001
Triglycerides, mmol/L 1.95
"
1.24 1.67
"
0.98 -0.001
Cholesterol-lowering medication, yes/no 153/297 45/223 -0.001
African-Brazilians/Caucasian-Brazilians 148/296 127/141 -0.001
firmed by ECG and/or cardiac enzymes in their
medical records.
Patients provided a detailed medical history and
underwent physical examination. Patients with blood
pressure G140/90 mm Hg and/or taking anti-hyper-
tensive medication were described as having hyper-
tension. Diabetes mellitus was defined as fasting
glucose level G7.0 mmol/L and/or when the patient
was taking anti-diabetic medication. Smoking was
defined as self-reported current or past smoking.
Patients who had a first-degree relative who had had
a myocardial infarct, sudden death and/or angina by
the age of 55 years for male or 65 years for female
were considered to have a positive early CAD family
history. African- and Caucasian-Brazilians were clas-
sified according to skin pigmentation on the inner
forearm and morphological facial characteristics, as
previously reported and validated by classical genetic
marks (11). All individuals provided written informed
consent approved by the Hospital Ethics Committee.
Blood samples were drawn for DNA extraction and
biochemical analysis from subjects who had fasted
for at least 12 h. A salting out procedure method was
used for DNA extraction as previously reported (12).
The Met55Leu and Gln192Arg PON1 polymorphisms
were detected using a mismatched primer set in a
multiplex PCR adapted from Motti et al. (13). The PCR
product was digested with HinfI and the fragment
bands were viewed after acrylamide gel electropho-
resis and ethidium bromide staining. Total choles-
terol, HDL-cholesterol and triglyceride levels were
measured by enzymatic methods using commercial
kits (Wiener Lab, Rosario, Argentina) on an auto-
analyzer. LDL-cholesterol levels were calculated using
the Friedwald formula (14).
Allele frequencies were estimated by gene count-
ing. The agreement of genotype frequencies with
Hardy-Weinberg expectations was tested by a x
2
goodness-of-fit test using Arlequin Program, version
2.000 (15). ANOVA or Student’s t-test was used to
compare quantitative variables between groups. The
lipoprotein levels were log transformed to reach nor-
mal distribution before ANOVA or t-test analysis, but
untransformed levels are presented in the Tables.
Allele frequency differences between cases and con-
trols were compared by Pearson x
2
test using the PEPI
program, version 4.0 (16). Odds ratio (OR) estimates
and multivariate logistic regression were performed
using SPSS version 10 (SPSS Inc., Chicago, IL, USA).
A p-value of -0.05 was considered statistically
significant.
Table 1 presents the clinical and demographic char-
acteristics of CAD cases and controls. There was a
higher prevalence of males, smokers, those with dia-
betes mellitus and early CAD family history, as well
as those who had higher triglyceride and lower HDL-
cholesterol levels among CAD cases than controls.
Cases and controls were similar with respect to
hypertension, total and LDL-cholesterol levels. How-
ever, in the same age range, CAD cases were some-
what older (55.5 years) than controls (52.3 years), and
there was a lower frequency of African-Brazilians
among cases compared to controls.
The Gln192Arg and Met55Leu PON1 genotype fre-
quencies differed between Caucasian- and African-
Brazilians. The 192ArgArg homozygous frequency
was higher, while the 55MetMet genotype frequency
was lower among African-Brazilians (28% and 16.7%,
respectively) compared to Caucasian-Brazilians
(17.8%, ps0.002 and 26.3%, ps0.010, respectively).
Among the control group, the genotype frequencies
were in accordance with those expected by Hardy-
Weinberg equilibrium, except for the Met55Leu vari-
ant in Caucasian-Brazilian males, which showed
deviation from equilibrium due to a lower heterozy-
gous frequency than expected.
Table 2 presents Met55Leu and Gln192Arg PON1
genotype frequencies in CAD cases and controls
according to ethnic and gender groups. In Caucasian-
Brazilians, the 55LeuLeu genotype frequency was
higher in CAD cases (51%) compared to controls
(30.3%; ps0.022) in females, but not males. Among
African-Brazilians, the Met55Leu polymorphism was
not associated with CAD. The Gln192Arg PON1 geno-
type frequencies were not associated with CAD in
African- and Caucasian-Brazilians for both male and
female subjects (Table 2).
Table 3 presents the triglyceride and HDL-choles-
terol levels among Gln192Arg PON1 genotypes in the
total sample of cases and controls according to gen-
der and ethnic group. Among Caucasian-Brazilians,
192GlnGln PON1 homozygotes presented the highest

876 Rios et al.: PON1-gender interaction on CAD risk in Brazilians
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Table 2 Met55Leu and Gln192Arg PON1 frequencies in Caucasian- and African-Brazilians CAD cases and controls according
to gender.
Male Female
Caucasian-Brazilians CAD cases Controls x
2
p CAD cases Controls x
2
p
Met55Leu genotypes ns196 ns65 ns100 ns76
MetMet 56 (28.6%) 21 (32.3%) 18 (18%) 20 (26.3%)
MetLeu 64 (32.7%) 15 (23.1%) 31 (31%) 33 (43.4%)
LeuLeu 76 (38.7%) 29 (44.6%) 51 (51%) 23 (30.3%)
2.124 0.346 7.632 0.022
OR*s0.786; 95% CI 0.4461.386; ps0.406 OR*s2.398; 95% CI 1.2814.490; ps0.006
Gln192Arg genotypes
GlnGln 92 (46.9%) 32 (49.2%) 36 (36%) 39 (51.3%)
GlnArg 68 (34.7%) 21 (32.3%) 45 (45%) 26 (34.2%)
ArgArg 36 (18.4%) 12 (18.5%) 19 (19%) 11 (14.5%)
0.136 0.934 4.142 0.126
OR**s0.994; 95% CIs0.4822.049; ps0.986 OR**s1.386; 95% CI 0.6163.119; ps0.430
African-Brazilians CAD cases Controls x
2
p CAD cases Controls x
2
p
Met55Leu genotypes ns99 ns56 ns49 ns71
MetMet 19 (19.2%) 11 (19.6%) 6 (12.2%) 10 (14.1%)
MetLeu 34 (34.3%) 20 (35.8%) 16 (32.7%) 26 (36.6%)
LeuLeu 46 (46.5%) 25 (44.6%) 27 (55.1%) 35 (49.3%)
0.049 0.976 0.393 0.822
OR*s1.076; 95% CI 0.5572.079; ps0.827 OR*s1.262; 95% CI 0.6082.620; ps0.532
Gln192Arg genotypes
GlnGln 45 (45.5%) 18 (32.1%) 13 (26.5%) 21 (29.6%)
GlnArg 25 (25.3%) 21 (37.5%) 24 (49%) 31 (43.7%)
ArgArg 29 (29.3%) 17 (30.4%) 12 (24.5%) 19 (26.8%)
3.381 0.184 0.332 0.847
OR**s0.950; 95% CI 0.4651.944; ps0.889 OR**s0.888; 95% CI 0.3842.049; ps0.780
OR, odds ratio; CI, confidence interval. *55LeuLeu genotype vs. 55Met carriers, **192ArgArg genotype vs. 192Gln carriers.
Table 3 Triglyceride and HDL-cholesterol levels among Gln192Arg PON1 genotypes in Caucasian- and African-Brazilians
according to gender.
Caucasian-Brazilians African-Brazilians
Female (ns176) Male (ns261) Female (ns120) Male (ns155)
Triglycerides, mmol/L
GlnGln 1.84
"
1.68 2.00
"
1.09 1.53
"
0.91 1.93
"
1.55
GlnArg 2.13
"
1.20 1.64
"
0.98 1.62
"
0.63 1.93
"
1.22
ArgArg 1.83
"
1.02 1.79
"
0.80 1.48
"
0.71 2.03
"
1.03
ps0.128 ps0.012 ps0.377 ps0.576
HDL-cholesterol, mmol/L
GlnGln 0.81
"
0.20 0.67
"
0.19 0.83
"
0.25 0.71
"
0.17
GlnArg 0.80
"
0.17 0.71
"
0.22 0.84
"
0.20 0.70
"
0.23
ArgArg 0.89
"
0.29 0.74
"
0.17 0.86
"
0.22 0.75
"
0.19
ps0.300 ps0.035 ps0.565 ps0.423
Results are for cases and controls combined.
triglyceride (ps0.012) and lowest HDL-cholesterol
levels (ps0.035) in males, but not in females. In Afri-
can-Brazilians, this polymorphism was not associated
with differences in lipid levels. No other lipoprotein
associations were detected with Gln192Arg PON1
genotypes and no lipid association at all was
observed for Leu55Met PON1 genotypes (data not
shown).
Table 4 shows the multivariate logistic regression
analyses for CAD risk among Caucasian-Brazilians.
55LeuLeu PON1 homozygotes were at increased CAD
risk (ORs2.852; ps0.003) and there was a significant
interaction between this genotype and gender
(ORs0.290; ps0.008). These effects were independ-
ent and corrected for other classic CAD risk factors
included in the regression model. Gln192Arg PON1
genotypes and other gene-smoking or gene-gender
interactions were not significant CAD predictors.
Among African-Brazilians, none of the PON1 geno-
types were significantly associated with CAD risk in
the multivariate logistic regression, even after cor-
recting for other CAD risk factors (data not shown).
This investigation of the effects of PON1 gene poly-
morphisms on angiographically assessed CAD in a
multi-ethnic Brazilian population has shown that
55LeuLeu PON1 homozygotes were at greater CAD
risk among Caucasian-Brazilians, irrespective of lipo-
protein levels and other classic CAD risk factors, as

Rios et al.: PON1-gender interaction on CAD risk in Brazilians 877
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Table 4 Multiple logistic regression for CAD risk in Caucasian-Brazilians.
Variable b SE Wald OR 95% CI p
Lower Upper
Age 0.065 0.016 16.488 1.068 1.034 1.102 -0.001
Male gender 1.427 0.319 20.020 4.165 2.230 7.782 -0.001
Early CAD history 0.555 0.247 5.025 1.742 1.072 2.829 0.025
Diabetes mellitus 1.376 0.361 14.520 3.959 1.951 8.036 -0.001
Hypertension 0.453 0.256 3.136 1.573 0.953 2.596 0.077
Smoking 0.622 0.238 6.830 1.862 1.168 2.969 0.009
HDL-cholesterol –1.353 0.603 5.044 0.258 0.079 0.842 0.025
LDL-cholesterol 0.061 0.115 0.286 1.063 0.849 1.332 0.593
Triglycerides 0.004 0.101 0.001 1.004 0.823 1.223 0.972
55Leu PON1 homozygous 1.048 0.351 8.921 2.852 1.434 5.673 0.003
55Leu PON1 homozygous=gender –1.239 0.470 6.932 0.290 0.115 0.729 0.008
Variables included in the model: age, gender, diabetes mellitus, hypertension, smoking (past and current), early CAD family
history, HDL-cholesterol, LDL-cholesterol and triglyceride levels (mmol/L), 55Leu PON1 homozygous state, 55Leu PON1 homo-
zygous state=gender, 55Leu PON1 homozygous state=smoking, 192Arg PON1 homozygous state, 192Arg PON1 homozygous
state=gender, and 192Arg PON1 homozygous state=smoking.
shown by the multivariate logistic regression analy-
sis. The present study corroborates a previous inves-
tigation in Southern Caucasian-Brazilians (17);
however, it further demonstrates that the 55LeuLeu
effect on CAD risk is influenced by gender in our
population.
The Met55Leu and Gln192Arg PON1 polymorphism
frequencies among African- and Caucasian-Brazilians
were similar to those previously reported in related
ethnic Brazilian populations from the Southern region
(17, 18), except for the 55Met allele frequency, which
was higher than those previously reported for Afri-
can-Brazilians from this region (18). Ancestral African
origins vary among African-Brazilians according to
region (19), which could explain this difference. The
Met55Leu genotype frequencies were not those
expected by Hardy-Weinberg equilibrium in Cauca-
sian-Brazilian males. It is unlikely that genotyping
errors could be the cause of this deviation, since we
confirmed the genotyping, and the deviation is
due to an excess of homozygous and not heterozy-
gous genotypes, as expected for this type of error. It
is more likely that the association of the 55LeuLeu
homozygous genotype with CAD could lead to devi-
ation of the homozygous genotype frequencies from
Hardy-Weinberg equilibrium.
The only previous study (20) of Gln192Arg and
Met55Leu PON1 polymorphism effects on angiogra-
phically assessed CAD in African-Americans showed
no genotype association with this disease. Among
Caucasian and Asian populations, 192Arg and/or
55Leu PON1 variants were positively associated with
increased CAD risk in some (17, 2125), but not all
studies (2628). The present report corroborates a
positive association between 55LeuLeu PON1 and
CAD risk in females, supporting a gender-specific
interaction. The exact cause of this PON1 gender-spe-
cific effect on CAD is not known, although a PON1
genotype effect on carotid atherosclerosis in females,
but not in males, has previously been demonstrated
(29). It is possible that hormonal differences between
genders could influence lipoprotein oxidation and
therefore the PON1 effect on atherosclerosis (30).
Smoking did not seem to be the cause of this geno-
type gender-specific effect, since the 55LeuLeu=
smoking interaction was not a significant CAD predic-
tor in the multivariate logistic model. Furthermore, as
HDL and PON1 synthesis are highly correlated (31)
and this HDL production is clearly influenced by ste-
roid hormones (32), it is possible that the PON1 geno-
type gender-specific effects could be, at least in part,
indirectly explained by hormonal influences on HDL
synthesis.
Although not associated with CAD, 192GlnGln
PON1 homozygotes presented lower HDL-cholesterol
and higher triglyceride levels among Caucasian-Bra-
zilian males, as previously reported in Caucasian-
Americans (29). The adverse lipoprotein profile for the
192GlnGln PON1 genotype contrasts with its high
enzyme activity in preventing LDL oxidation (8), which
could be a possible explanation for the lack of asso-
ciation with CAD shown in the present study.
In summary, this study on angiographically
assessed CAD in a multi-ethnic Brazilian sample dem-
onstrates that 55LeuLeu PON1 homozygotes are at
increased CAD risk among Caucasian- but not African-
Brazilians, and this effect is influenced by gender,
being more significant among females. Subjects
homozygous for 192GlnGln PON1 had lower HDL-
cholesterol and higher triglyceride levels in Cauca-
sian-Brazilian males, but this genotype was not
associated with CAD risk.
Acknowledgements
This study was supported by Fundaca˜ o de Amparo a Pes-
¸
quisa do Estado da Bahia (FAPESB) and by Conselho Nacio-
nal de Desenvolvimento Cientı´fico e Tecnolo´ gico (CNPq).
References
1. Witztum JL, Steinberg D. Role of oxidized low density
lipoprotein in atherogenesis. J Clin Invest 1991;88:1785
92.

878 Rios et al.: PON1-gender interaction on CAD risk in Brazilians
Article in press - uncorrected proof
2.
Navab M, Berliner JA, Watson AD, Hama SY, Territo MC,
Lusis AJ, et al. The Yin and Yang of oxidation in the
development of the fatty streak. A review based on the
1994 George Lyman Duff Memorial Lecture. Arterioscler
Thromb Vasc Biol 1996;16:83142.
3.
Blatter MC, James RW, Messmer S, Barja F, Pometta D.
Identification of a distinct human high-density lipopro-
tein subspecies defined by a lipoprotein-associated pro-
tein, K-45. Identity of K-45 with paraoxonase. Eur J
Biochem 1993;211:8719.
4.
Kelso GJ, Stuart WD, Richter RJ, Furlong CE, Jordan-
Starck TC, Harmony JA. Apolipoprotein J is associated
with paraoxonase in human plasma. Biochemistry 1994;
33:8329.
5.
Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S, et al.
Mice lacking serum paraoxonase are susceptible to
organophosphate toxicity and atherosclerosis. Nature
1998;394:2847.
6.
Rozenberg O, Rosenblat M, Coleman R, Shih DM, Avi-
ram M. Paraoxonase (PON1) deficiency is associated
with increased macrophage oxidative stress: studies in
PON1-knockout mice. Free Radic Biol Med 2003;34:
77484.
7.
Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN. The
human serum paraoxonase/arylesterase gene (PON1) is
one member of a multigene family. Genomics 1996;33:
498507.
8.
Mackness B, Mackness MI, Arrol S, Turkie W, Durrington
PN. Effect of the human serum paraoxonase 55 and 192
genetic polymorphisms on the protection by high den-
sity lipoprotein against low density lipoprotein oxidative
modification. FEBS Lett 1998;423:5760.
9.
Wheeler JG, Keavney BD, Watkins H, Collins R, Danesh
J. Four paraoxonase gene polymorphisms in 11212 cas-
es of coronary heart disease and 12786 controls: meta-
analysis of 43 studies. Lancet 2004;363:68995.
10.
Rios DL, D’Onofrio LO, Souza JK, Queiroz AM, Raduy-
Maron L, Silva-Neto N, et al. Smoking-dependent and
haplotype-specific effects of endothelial nitric oxide
synthase gene polymorphisms on angiographically
assessed coronary artery disease in Caucasian- and Afri-
can-Brazilians. Atherosclerosis wEpub ahead of printx, doi
10.1016/j.atherosclerosis.2006.05.041.
11.
Azevedo ES. Subgroup studies of black admixture within
a mixed population of Bahia, Brazil. Ann Hum Genet
1980;44:5560.
12.
Lahiri DK, Nurnberger JI Jr. A rapid non-enzymatic
method for the preparation of HMW DNA from blood for
RFLP studies. Nucleic Acids Res 1991;19:5444.
13.
Motti C, Dessi M, Gnasso A, Irace C, Indigeno P, Ange-
lucci CB, et al. A multiplex PCR-based DNA assay for the
detection of paraoxonase gene cluster polymorphisms.
Atherosclerosis 2001;158:3540.
14.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of
the concentration of low-density lipoprotein cholesterol
in plasma, without use of the preparative ultracentrifuge.
Clin Chem 1972;18:499502.
15.
Schneider S, Roessli D, Excoffier L. Arlequin ver. 2000:
a software for population genetics data analysis. Genet-
ics data analysis. Geneva: Genetics and Biometry Labo-
ratory, University of Geneva, 2000.
16.
Abramson JH, Gahlinger PM. Computer programs for
epidemiologists: PEPI. Version 4.0. Salt Lake City, UT:
Sagebrush Press, 2001.
17.
Oliveira SA, Mansur AP, Ribeiro CC, Ramires JA, Anni-
chino-Bizzacchi JM. PON1 M/L55 mutation protects high-
risk patients against coronary artery disease. Int J
Cardiol 2004;94:737.
18. Allebrandt KV, Souza RL, Chautard-Freire-Maia EA. Var-
iability of the paraoxonase gene (PON1) in Euro- and
Afro-Brazilians. Toxicol Appl Pharmacol 2002;180:1516.
19. Silva WA, Bortolini MC, Schneider MP, Marrero A, Elion
J, Krishnamoorthy R, et al. MtDNA haplogroup analysis
of black Brazilian and sub-Saharan populations: impli-
cations for the Atlantic slave trade. Hum Biol 2006;78:
2941.
20. Chen Q, Reis SE, Kammerer CM, McNamara DM, Holub-
kov R, Sharaf BL, et al. Association between the severity
of angiographic coronary artery disease and paraoxo-
nase gene polymorphisms in the National Heart, Lung,
and Blood Institute-sponsored Women’s Ischemia Syn-
drome Evaluation (WISE) study. Am J Hum Genet 2003;
72:1322.
21. Martinelli N, Girelli D, Olivieri O, Cavallari U, Biscuola M,
Trabetti E, et al. Interaction between metabolic syn-
drome and PON1 polymorphisms as a determinant of
the risk of coronary artery disease. Clin Exp Med 2005;
5:2030.
22. Scacchi R, Gambina G, Martini MC, Broggio E, Vilardo
T, Corbo RM. Different pattern of association of paraoxo-
nase Gln192Arg polymorphism with sporadic late-
onset Alzheimer’s disease and coronary artery disease.
Neurosci Lett 2003;339:1720.
23.
Osei-Hyiaman D, Hou L, Mengbai F, Zhiyin R, Zhiming
Z, Kano K. Coronary artery disease risk in Chinese type
2 diabetics: is there a role for paraoxonase 1 gene
(Q192R) polymorphism? Eur J Endocrinol 2001;144:
63944.
24.
Pfohl M, Koch M, Enderle MD, Kuhn R, Fullhase J,
Karsch KR, et al. Paraoxonase 192 Gln/Arg gene poly-
morphism, coronary artery disease, and myocardial
infarction in type 2 diabetes. Diabetes 1999;48:6237.
25.
Ruiz J, Blanche H, James RW, Garin MC, Vaisse C, Char-
pentier G, et al. Gln-Arg192 polymorphism of paraoxo-
nase and coronary heart disease in type 2 diabetes.
Lancet 1995;346:86972.
26.
Arca M, Ombres D, Montali A, Campagna F, Mangieri E,
Tanzilli G, et al. PON1 L55M polymorphism is not a pre-
dictor of coronary atherosclerosis either alone or in com-
bination with Q192R polymorphism in an Italian
population. Eur J Clin Invest 2002;32:915.
27.
Gardemann A, Philipp M, Hess K, Katz N, Tillmanns H,
Haberbosch W. The paraoxonase Leu-Met54 and Gln-
Arg191 gene polymorphisms are not associated with the
risk of coronary heart disease. Atherosclerosis 2000;
152:42131.
28.
Cascorbi I, Laule M, Mrozikiewicz PM, Mrozikiewicz A,
Andel C, Baumann G, et al. Mutations in the human
paraoxonase 1 gene: frequencies, allelic linkages, and
association with coronary artery disease. Pharmaco-
genetics 1999;9:75561.
29.
Srinivasan SR, Li S, Chen W, Tang R, Bond MG, Boer-
winkle E, et al. Q192R polymorphism of the paraoxonase
1 gene and its association with serum lipoprotein
variables and carotid artery intima-media thickness in
young adults from a biracial community. The Bogalusa
Heart Study. Atherosclerosis 2004;177:16774.
30.
Sack MN, Rader DJ, Cannon RO III. Oestrogen and inhi-
bition of oxidation of low-density lipoproteins in post-
menopausal women. Lancet 1994;343:26970.
31.
Shih DM, Gu L, Hama S, Xia YR, Navab M, Fogelman
AM, et al. Genetic-dietary regulation of serum paraoxo-
nase expression and its role in atherogenesis in a mouse
model. J Clin Invest 1996;97:16309.
32.
Knopp RH, Zhu X. Multiple beneficial effects of estrogen
on lipoprotein metabolism. J Clin Endocrinol Metab 1997;
82:39524.
Received January 15, 2007, accepted March 1, 2007

Citations
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Journal ArticleDOI
TL;DR: This review provides an extended overview on the current genetic-epidemiological evidence from association studies on genes involved in HDLC metabolism and reviews the recent findings from genome-wide association studies which have identified new genes influencing HDLC levels.

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TL;DR: It is demonstrated that the genetic risk for heart diseases is associated with the PON1 gene polymorphisms, L55M polymorphism is a risk factor and Q192R polymorphisms is protective in certain populations.

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TL;DR: No correlation of PON 192 or 55 polymorphism was found with oxidized LDL suggesting that presence of other antioxidant factors may be of equal importance in preventing LDL oxidation, and the present study looks at PON192 and55 polymorphism among hospitalized Asian Indian patients with myocardial infarction and their association with circulating oxidized cholesterol and antioxidant status.
Abstract: Results: Patients with MI had significantly higher oxidized LDL ( P<0.05) and lower total antioxidant capacity (P<0.001) as compared to controls. Oxidized LDL correlated with total cholesterol, LDL and Apo B in patients. B allele frequency of the codon 192 polymorphism in paraoxonase gene was higher in cases as compared to controls and odds ratio of developing the MI with BB genotype versus AA genotype was 2.37, (P=0.044). Codon 55 polymorphism in paraoxonase gene was not associated with CAD. There was no difference in oxidized LDL between the different genotypes of PON192 and PON55. Interpretation & conclusions: Although PON192 polymorphism was associated with CAD, no correlation of PON192 or 55 polymorphism was found with oxidized LDL suggesting that presence of other antioxidant factors may be of equal importance in preventing LDL oxidation.

37 citations

References
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Journal ArticleDOI
TL;DR: A method for estimating the cholesterol content of the serum low-density lipoprotein fraction (Sf0-20) is presented and comparison of this suggested procedure with the more direct procedure, in which the ultracentrifuge is used, yielded correlation coefficients of .94 to .99.
Abstract: A method for estimating the cholesterol content of the serum low-density lipoprotein fraction (Sf0-20) is presented. The method involves measurements of fasting plasma total cholesterol, triglyceride, and high-density lipoprotein cholesterol concentrations, none of which requires the use of the preparative ultracentrifuge. Comparison of this suggested procedure with the more direct procedure, in which the ultracentrifuge is used, yielded correlation coefficients of .94 to .99, depending on the patient population compared.

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Abstract: Evidence to support an important role of oxidative modification in mediating the atherogenicity of LDL continues to grow. New hypotheses suggest mechanisms by which Ox-LDL or products of Ox-LDL can affect many components of the atherogenic process, including vasomotor properties and thrombosis, as well as lesion initiation and progression itself. These ideas suggest new approaches, that in combination with lowering of plasma cholesterol, could lead to the prevention of atherosclerosis and its complications.

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TL;DR: The procedure reported here is the most economical, safe and rapid for preparation of DNA from whole blood and eliminates completely the use of proteinase K treatment.
Abstract: In genetic linkage studies using the restriction fragment length polymorphism (RFLP) technique, it is essential to process effectively large numbers of blood samples. One of the problems faced when extracting DNA by standard methods is the requirement of deproteinizing cell digests with hazardous organic solvents like phenol, chloroform and isoamyl alcohol (1-3). The method described in this report avoids the use of any organic solvents. This is achieved by salting out the cellular proteins by dehydration and precipitation with a saturated sodium chloride solution (4). Most of the procedures also involve prolonged incubation with proteinase K (1, 4, 5). Our procedure eliminates completely the use of proteinase K treatment. The method reported here is the most economical, safe and rapid for preparation of DNA from whole blood.

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Abstract: ABD active disease (abdomen) 1=normal, 2=suspicious, 3=abnormal, 4=unknown ACNE acne Grade 1-5 AD history of active disease 1=normal, 2=suspicious, 3=abnormal, 4=unknown AGE age (years) AMPM_B Time blood sample drawn 1=AM 2=PM AMPM_F Time of last food intake 1=AM 2=PM APO_A1 Apo A1 mg/100ml ARM_BP1 arm used for blood pressure 1=left, 2=right, 9=unknown ARM_BP2 arm used for blood pressure 1=left, 2=right, 9=unknown ARM_BP3 arm used for blood pressure 1=left, 2=right, 9=unknown ARM_SS arm used to measure skinfold, subscapular 1=right, 2=left, 9=unknown

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Abstract: Overview of the concept ofoxidative modification ofLDL There can be no doubt now that there is a continuum of increasing risk for complications ofatherosclerosis when plasma cholesterol levels exceed 160-180 mg/dl. Many types of experimental and clinical evidence substantiate the "cholesterol hypothesis." Many primary and secondary prevention trials, including the recent angiographic trials(CLAS andFATS) document that reduction of plasma cholesterol is as powerful as has been predicted in slowing the progression and clinical expression ofcoronary atherosclerosis. However, the cellular and molecular mechanisms linking hypercholesterolemia to atherogenesis and its sequelae remain unclear. Iflowering ofLDL is efficacious in ameliorating the atherogenic process, why then should one bother to understand the mechanisms? Simply because loweringLDL will not be a total solution. Although it may be true that ifcholesterol levels were reduced to < 150 mg/dl there would be little if any coronary artery disease (CAD),' it is not likely that this will occur any time soon. At any given level ofLDL there is great variability in the clinical expression of the disease. Patients with heterozy

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Q1. What contributions have the authors mentioned in the paper "Paraoxonase 1 gene polymorphisms in angiographically assessed coronary artery disease: evidence for gender interaction among brazilians" ?

The authors studied the Met55Leu and Gln192Arg PON1 polymorphisms in 712 patients ( 437 Caucasianand 275 African-Brazilians ) who underwent coronary angiography. This report shows that the 55LeuLeu PON1 genotype increases CAD risk among female * Corresponding author: Dr. Domingos Lázaro S. Rios, Laboratório de Genética Molecular, Departamento de Ciências Biológicas-DCB, Universidade Estadual do Sudoeste da Bahia-UESB, Avenida José Moreira Sobrinho, s/n, Bairro-Jequiezinho, 45200-000 Jequié, BA, Brazil Phone: q55-73-35289660, Fax: q55-73-35256683, E-mail: domingosrios @ hotmail.