ArticlePDF Available

The CC genotype of the angiotensin II type I receptor gene independently associates with acute myocardial infarction in a Tunisian population

Authors:

Abstract and Figures

Acute myocardial infarction (AMI) is a multifactorial disease influenced by environmental and genetic factors. The aim of this study was to assess the association of angiotensin II type 1 receptor (ATR1) gene polymorphisms with AMI as well as to evaluate the role of serum angiotensin-converting enzyme (ACE) activity and that of cardiac troponin I (cTnI) in Tunisian AMI patients. One hundred and eighteen AMI patients were compared to 150 healthy controls. ATR1 genotypes were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The ATR1 A1166C polymorphism was significantly associated with AMI (p = 0.024). CC genotype and C allele frequencies were associated with increased AMI risk [CC vs. AC and AA: OR = 2.06; p = 0.045; 95 % CI (1.02-4.18); C vs. A: OR = 1.68; p = 0.004; 95 % CI (1.17-2.41)]. By multivariate logistic regression analysis, CC genotype, hypertension, diabetes, serum ACE activity and peak-cTnI were significant independent predictors of AMI. Increased serum ACE activity and cTnI peak levels were associated with the CC genotype in AMI patients. In conclusion, the ATR1 A1166C polymorphism is associated with AMI and the CC genotype associated with increased ACE activity and cTnI levels appear to predispose for AMI risk.
Content may be subject to copyright.
http://jra.sagepub.com/
System
Journal of Renin-Angiotensin-Aldosterone
http://jra.sagepub.com/content/early/2011/02/08/1470320310391833
The online version of this article can be found at:
DOI: 10.1177/1470320310391833
published online 17 February 2011Journal of Renin-Angiotensin-Aldosterone System
Hammami
Sounira Mehri, Sinda Mahjoub, Josef Finsterer, Amira Zaroui, Rachid Mechmeche, Bruno Baudin and Mohamed
myocardial infarction in a Tunisian population
The CC genotype of the angiotensin II type I receptor gene independently associates with acute
Published by:
http://www.sagepublications.com
can be found at:Journal of Renin-Angiotensin-Aldosterone SystemAdditional services and information for
http://jra.sagepub.com/cgi/alertsEmail Alerts:
http://jra.sagepub.com/subscriptionsSubscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
by guest on March 9, 2011jra.sagepub.comDownloaded from
Article
Introduction
Acute myocardial infarction (AMI) is a major cause of
morbidity and mortality worldwide. AMI is a multifactorial
disease influenced by environmental and genetic factors.
From being an illness prevalent predominantly in devel-
oped countries, AMI is now becoming increasingly more
common in developing countries. Contemporary manage-
ment of AMI is based on extensive data about epidemiol-
ogy, basic science, and clinical findings. These studies have
highlighted the contribution of lifestyle factors to the inci-
dence of AMI; explored genetic underpinnings; and pro-
vided clinical methods and biomarkers for early diagnosis
and risk stratification.1
Components of the renin angiotensin system (RAS) are
important determinants of the vasomotor tone. Epidemiologic
evidence suggests that these components are involved in the
pathogenesis of coronary artery disease and AMI. As an
example, polymorphisms of the angiotensin II type 1 recep-
tor (ATR1) gene have been shown to be associated with the
occurrence of AMI. The influence of these ATR1 gene poly-
morphisms on the risk of AMI may be attributed, at least in
part, to a deleterious effect on coronary vasomotion. Most of
the known effects of angiotensin II (Ang II), the powerful
effector peptide of the RAS, are mediated by at least two
different receptor types that are involved in the regulation of
cell growth, fibrosis, and inflammatory response: ATR1 and
Ang II type 2 receptors (ATR2).2 ATR1 is expressed in dif-
ferent organs including the heart, skeletal muscle, brain,
Journal of the Renin-Angiotensin-
Aldosterone System
XX(X) 1 –6
© The Author(s) 2011
Reprints and permission:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1470320310391833
jra.sagepub.com
1
Laboratoire de Biochimie, UR Human Nutrition and Metabolic
Disorders, Faculté de Médecine de Monastir, Tunisie.
2
Unité de Recherche, Epidémiologie Génétique et Moléculaire, Faculté
de Médecine de Tunis, Tunisie.
3
Krankenanstalt Rudolfstiftung Vienne et Université de Danube Krems,
Autriche.
4
Service des Explorations Fonctionnelles Cardiologiques, Hôpital La
Rabta de Tunis, Tunisie.
5 Service de Biochimie A, Hôpital Saint-Antoine, Paris, France.
Corresponding author:
Mohamed Hammami, Laboratoire de Biochimie, UR Human
Nutrition and Metabolic Disorders, Faculté de Médecine de
Monastir, Tunisie.
Email: mohamed.hammami@fmm.rnu.tn
The CC genotype of the angiotensin II
type I receptor gene independently
associates with acute myocardial
infarction in a Tunisian population
Sounira Mehri1,2, Sinda Mahjoub2, Josef Finsterer3, Amira Zaroui4,
Rachid Mechmeche4, Bruno Baudin5 and Mohamed Hammami1
Abstract
Acute myocardial infarction (AMI) is a multifactorial disease influenced by environmental and genetic factors. The aim of
this study was to assess the association of angiotensin II type 1 receptor (ATR1) gene polymorphisms with AMI as well
as to evaluate the role of serum angiotensin-converting enzyme (ACE) activity and that of cardiac troponin I (cTnI) in
Tunisian AMI patients. One hundred and eighteen AMI patients were compared to 150 healthy controls. ATR1 genotypes
were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The ATR1 A1166C
polymorphism was significantly associated with AMI (p = 0.024). CC genotype and C allele frequencies were associated
with increased AMI risk [CC vs. AC and AA: OR = 2.06; p = 0.045; 95 % CI (1.02–4.18); C vs. A: OR = 1.68; p = 0.004; 95
% CI (1.17–2.41)]. By multivariate logistic regression analysis, CC genotype, hypertension, diabetes, serum ACE activity
and peak-cTnI were significant independent predictors of AMI. Increased serum ACE activity and cTnI peak levels were
associated with the CC genotype in AMI patients. In conclusion, the ATR1 A1166C polymorphism is associated with AMI
and the CC genotype associated with increased ACE activity and cTnI levels appear to predispose for AMI risk.
Keywords
Acute myocardial infarction (AMI), angiotensin II type 1 receptor (ATR1) gene, polymorphism, cardiac troponin I (cTnI),
serum angiotensin-converting enzyme (ACE) activity
by guest on March 9, 2011jra.sagepub.comDownloaded from
2 Journal of the Renin-Angiotensin-Aldosterone System XX(X)
liver, lung, and adrenal gland. The expression of ATR2 is
abundant in fetal tissues, but scanty in adult tissues.3
Furthermore, ATR2 works cardioprotectively against
ATR1.4 The receptors belong to the superfamily of the G
protein-coupled receptors, and, in case of the ATR1 recep-
tor, coupling occurs via Gq proteins. Consequently, stimu-
lation of ATR1 receptors activates phospholipase C,
increases the levels of diacylglycerol (DAG) and inositol
triphosphate (IP3), elevates the intracellular Ca2+ concen-
tration, and activates several kinases modulating cell func-
tions.5 Ang II acts as a mitogen in vascular smooth muscle
cells by activating several signalling pathways, such as that
of phospholipase C, phospholipase A2, and phospholipase
D; as well as activating a large number of kinases, such as
tyrosine kinases, mitogen-activated protein kinases
(MAPKs), c-src kinase, Janus-associated tyrosine kinase,
and receptors with tyrosine-kinase activity. Ang II also
stimulates transcription factors, such as the activating pro-
tein, signal transduction and transcription activators
(STATs), and the nuclear factor kappa B (NFκB).6
The A1166C polymorphism of the ATR1 gene is located
at the 5’ end of the 3’ untranslated region and does not alter
potential messenger (m)RNA polyadenylation or destabili-
zation signals.7 There are indications that homozygosity of
the A1166C polymorphism (CC genotype) is associated
with a higher incidence of AMI.8 Disease prevention is an
important strategy for reducing the overall burden of AMI,
and the identification of markers for disease risk is the key
for both risk prediction and potential intervention to reduce
the chance of future events. At the edge of genetically-
designed pharmacotherapy, a more profound knowledge of
this issue is needed. This study sought to assess the poten-
tial association of ATR1 A1166C gene polymorphism with
AMI as well as to evaluate the role of serum ACE activity
and that of cardiac troponin I (cTnI) in Tunisian patients
with AMI. In addition, we compared this Tunisian popula-
tion with other populations and investigated the relation-
ship between the studied parameters and the classical risk
factors.
Design and methods
Populations
Included were 118 unrelated patients with a history of a
recent AMI recruited at the Department of Cardiology of
Rabta Hospital, Tunis, Tunisia between January 2005 and
November 2007. All patients were admitted with an acute
coronary syndrome and underwent coronary angiography.
The diagnosis of AMI was established by cardiologists upon
typical complaints, typical ECG abnormalities, and elevated
AMI biomarkers. All patients experienced their first AMI
without a previous history of coronary artery disease. Mean
age was 62.1 ± 11.9 years. Family history, cardiovascular
risk factors and current treatment were obtained from each
patient using a standard protocol. The study was approved
by the hospital’s ethical committee, and informed consent
was obtained from all healthy controls and patients before
their enrolment.
The body mass index (BMI) was calculated as weight
divided by height.2 Arterial hypertension was diagnosed if
the systolic blood pressure was elevated >140 mmHg or the
diastolic blood pressure >90 mmHg or if antihypertensive
drugs were currently used.
One hundred and fifty healthy individuals (89 men
and 61 women; mean age 60.7 ± 10.3 years), matched for
sex, age, and geographic origin, were enrolled as healthy
controls.
Biochemical measurements
Venous blood (5 ml) was collected in a plain test tube and
serum was separated. Biochemical measurements were car-
ried out according to validated methods. Serum glucose
concentration was determined using an enzymatic kit
(Glucose oxidase, Randox, Antrim, UK), glycosylated
hemoglobin (HbA1c) by an exchange microcolumn chro-
matographic procedure (Biosystems, Barcelona, Spain),
total cholesterol and triglycerides by enzymatic methods
using Randox reagents, and LDL and HDL cholesterol were
determined as described by Smaoui et al.9 Serum ACE
activity was determined in AMI patients who did not take
ACE-inhibitors or angiotensin II receptor antagonists. The
serum was stored at -20°C until assay. Serum ACE activity
was determined on the automated Synchron CX-4 DE
(Beckman-Coulter) analyser with N-[3-(2-furyl)acryloyl]-
L-phenylalanyl-L-glycyl-L-glycine (FAPGG) as a sub-
strate.10 We previously reported on this automated
determination of serum ACE activity and demonstrated the
reliability and simplicity that makes it suitable for routine
use and for clinical investigations.11 One unit (1 U) of ACE
activity is the amount of enzyme that hydrolyses 1 µmol of
FAPGG per min. The complete hydrolysis of 1 mmol of
FAPGG to furylacryloyl-Phe and Gly-Gly by ACE at 10 µg/
mL (60 min at 37ºC) led to a maximal decrease of the
absorbance at 340 nm. The final concentrations were 0.8
mM FAPGG in 0.3 M NaCl, 25 mM HEPES
[4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid] pH
8.2 buffer. A blank was performed with 20 µL of pure water
in place of sample and its kinetic measure deducted from
that of the assays; all the assays were realized in duplicates.
Cardiac troponin I (cTnI) (ng/ml) was measured upon
patient arrival and at 6, 12, 24, 48 and 96 hours after reper-
fusion. cTnI was determined using AxSYM Troponin-I
ADV (Abbott Laboratories, Abbott Park, USA) which is a
three-step assay, based on micro-particle enzyme immu-
noassay (MEIA) technology with an analytical sensitivity
of 0.02 ng/ml and a diagnostic cut-off for myocardial
by guest on March 9, 2011jra.sagepub.comDownloaded from
Mehri et al. 3
infarction of 0.40 ng/ml. The 99th percentile was 0.04 ng/
ml as described by the manufacturer. The assay was
designed to have a precision <10% total coefficient of vari-
ation with 95% confidence for concentrations between 0.27
ng/ml and 4.00 ng/ml. Peak-cTnI was determined.
ATR1 genotyping protocols
Total DNA was extracted using the standard phenol-chloro-
form technique. To detect the A1166C polymorphism, PCR
amplification was performed under previously described
conditions12 and PCR products were digested by AFlII.
Statistical analysis
Allele and genotype frequencies were obtained by direct
counting. Data that are not normally distributed are repre-
sented by the median value (25th to 75th interquartile
range). Continuous variables according to a Gaussian distri-
bution are expressed as the mean and standard deviation
(mean ± SD) and compared using the unpaired Student’s
t-test. To determine whether serum ACE-activity or peak-
cTnI were independently associated with the severity of
AMI, binary logistic regression analysis, which allows
adjustment for confounding factors, was performed. A value
of p < 0.05 was considered statistically significant. All sta-
tistics were calculated by the SPSS 11.0 statistical software
package for social sciences (SPSS, Chicago, USA).
Results
Patients’ characteristics are shown in table 1. There was no
significant difference in either the age or gender distribution
between the two groups included. The prevalence of arterial
hypertension (HTA), dyslipidemia, and diabetes were signifi-
cantly increased in AMI patients as compared to healthy con-
trols. Diastolic blood pressure (DBP), systolic blood pressure
(SBP), triglyceride, total cholesterol, LDL-cholesterol, HDL-
cholesterol, HbA1c and fasting glucose levels were also
higher in AMI patients than in healthy controls.
ATR1 A1166C genotype and allele frequencies of
patients and controls are presented in table 2. The distribu-
tion of the ATR1 genotypes was in agreement with the
Hardy–Weinberg equilibrium. The frequency of the A1166C
polymorphism was significantly different between patients
and controls (p = 0.024). Individuals with the CC genotype
had a significantly higher risk of AMI as compared to those
who carried the AC or AA genotypes [ATR1 CC vs. AC and
AA; OR = 2.06; p = 0.045; 95 % CI (1.02–4.18)]. In con-
trast, to those with CC genotype, individuals with AA geno-
type had a significantly lower risk of AMI as compared with
those who carried the AC or CC genotype [ATR1 AA vs. AC
and CC; OR = 0.54; p = 0.015; 95 % CI (0.33–0.88)].
Although the AC genotype was more frequent in AMI
patients (44.9%) than in controls (38.7%), the difference
was not statistically significant (p = 0.306). The distribution
of the A1166C polymorphism in AMI patients and controls
compared to other populations is shown in table 3. The CC
genotype was most frequent in AMI patients from Tunisia
(18.6%) as compared to Brazilian (10%), Turkish (9.8%), or
South Indian (8.4%) patients.
Table 1. Biochemical and clinical characteristics of AMI
patients compared to healthy controls
AMI patients
(n = 118)
Healthy
controls
(n = 150)
p
Mean age (years) 62.1±11.9 60.7±10.3 0.304
Sex (male/female) 67/51 89/61 0.383
BMI (kg/m2) 27.9±5.4 26.8±4.4 0.063
Smokers (%) 81 (68.6) 92 (61.3) 0.400
Fasting glucose (mmol/L) 6.3±1.5 4.8±1.4 0.000
Diabetes (%) 57 (48.3) 7 (4.7) 0.000
HbA1c (%) 7.5±2.6 5.3±1.7 0.000
Hypertension (%) 63 (53.4) 27 (18) 0.000
DBP (mmHg) 93.6±15.7 85.3±6.9 0.000
SBP (mmHg) 151.2±22.7 131.4±8.5 0.000
Dyslipidemia (%) 24 (20.3) 11 (7.3) 0.000
Total cholesterol (mmol/L) 8.2±1.6 4.3±0.9 0.000
HDL-C (mmol/L) 1.9±0.2 1.1±0.2 0.000
LDL-C (mmol/L) 5.8±1.5 2.5±0.7 0.000
Triglycerides (mmol/L)a2 (1.8-2.1) 1.2 (1-1.5) 0.000
aExpressed as median (IR); BMI: body mass index, SBP: systolic blood
pressure; DBP: diastolic blood pressure; HDL: high-density lipoprotein;
LDL: low-density lipoprotein.
Table 2. Angiotensin II type 1 receptor A1166C polymorphism.
Distribution and allele frequency in AMI patients and controls
ATR1 A1166C
Polymorphism
AMI patients
(n = 118)
Healthy controls
(n = 150) OR
CC (%) 22 (18.6) 15 (10) OR = 2.06
(1.02–4.18),
p = 0.045
AC (%) 53 (44.9) 58 (38.7) OR = 1.29
(0.79–2.1),
p = 0.306
AA (%) 43 (36.4) 77 (51.3) OR = 0.54
(0.33–0.88),
p = 0.015
C (%) 97 (41.1) 88 (29.3) OR = 1.68
(1.17–2.41),
p = 0.004
A (%) 139 (58.9) 212 (70.7) OR = 0.59
(0.41–0.85),
p = 0.004
OR: Odds ratio, 95% CI (in parentheses)
by guest on March 9, 2011jra.sagepub.comDownloaded from
4 Journal of the Renin-Angiotensin-Aldosterone System XX(X)
Multiple regression analysis was performed to extract
factors determining the severity of AMI. The model included
conventional risk factors, such as age, sex, BMI, triglycer-
ide, LDL- and HDL-cholesterol, SBP, DBP, peak-cTnI,
HTA, diabetes, smoking, obesity, dyslipidemia, serum ACE
activity, and new risk factors, such as the A1166C polymor-
phism. Multivariate analysis showed that CC genotype,
HTA, diabetes, serum ACE activity and peak-cTnI are inde-
pendent risk factors for AMI with the following odds ratios
(95% CI): CC genotype 2.03 (1.92–2.3) (p = 0.013); HTA
4.3 (3.7–5.45) (p < 0.001); diabetes 2.1 (1.9–3.45) (p <
0.001); serum ACE activity 3.08 (2.7–3.45) (p < 0.001); and
peak-cTnI 4.56 (3.68–5.44) (p = 0.001). Spearman’s corre-
lation rank was then used to evaluate the correlations
between serum ACE activity and other parameters in AMI
patients (as defined in table 1). Serum ACE activity was cor-
related with peak-cTnI (r = 0.437; p = 0.001).
Baseline characteristics of the patients’ group with
regard to the ATR1 genotype are summarised in table 4.
The results showed that the triglyceride, serum ACE activ-
ity and peak-cTnI were significantly higher in AMI patients
with the CC genotype compared with patients with the AC
or AA genotype (table 4 and figure 1).
Discussion
This study showed that A1166C gene polymorphism is a
genetic risk factor for AMI. Individuals with the AA geno-
type are highly protected against AMI, whereas subjects
with the CC genotype have an increased risk of developing
an AMI. Furthermore, the multiple logistic regression
analysis results showed a significant association of CC
genotype and AMI even in the presence of all other clinical
factors analysed in this study. The frequency of the C allele
in controls and AMI patients was highest in the Tunisian
population as compared to the South Indian, Turkish, and
Brazilian populations.13-15 There are controversial reports
regarding the role of the A1166C polymorphism as a risk
factor for AMI. Some studies found a positive correla-
tion8,16,17 but others did not.13-15,18 Other studies reported
the CC genotype to be associated with HTA,19 coronary
heart disease,20 and stroke.21 The A1166C polymorphism
has been also studied in type 2 diabetic patients from
India.22 Interestingly, we found that diabetes and HTA
were the most important risk factors for AMI in our popu-
lation. Positive associations between the A1166C poly-
morphism and disease may be the result of linkage
disequilibrium with another polymorphism of functional
importance, either within the ATR1 gene or within one
nearby.23 The A/C transversion per se does not characterise
any functional diversity. Although there is no evidence to
support this hypothesis, this polymorphism can be consid-
ered as a possible marker, in linkage disequilibrium with
other functionally relevant genetic variants affecting the
structure or expression of the ATR1.23 It is therefore impor-
tant to identify the variant of the gene responsible for the
biological effect.
The efficacy of ACE inhibition and Ang II receptor
blockade demonstrate the important role of the RAS in the
pathogenesis of coronary arteriosclerosis and its related
disorders.24 We have previously shown in a Tunisian popu-
lation that the DD genotype of the ACE I/D polymorphism
is associated with higher serum ACE activity in AMI.25
Subjects homozygous for the I allele of the ACE I/D poly-
morphism had the lowest serum ACE levels; heterozygotes
had intermediate values, and homozygotes for the D allele
the highest ACE levels. To improve understanding of the
role of the CC genotype in AMI, the relationship between
A1166C polymorphism, serum ACE activity, and peak-
cTnI was studied. The CC genotype in AMI patients seems
to be associated with significantly higher serum ACE activ-
ity and elevated peak-cTnI levels as compared to subjects
with the AA and AC genotypes, suggesting that the A1166C
polymorphism affects serum ACE activity and the activa-
tion of cardiac sympathetic activity, eventually leading to
cardiac myocyte death. This could be one mechanism for
the cTnI-release. Furthermore, multiple logistic regression
analysis revealed that the serum ACE activity and peak-
cTnI were independent predictors of AMI. The RAS is
implicated in this process through the ATR1 gene polymor-
phism, suggesting that blocking of the RAS might have
beneficial effects on arterial wall structure and function.
Most of the known physiological effects of RAS
Table 3. Distribution of the ATR1 A1166C genotypes in AMI patients and controls compared to other populations
Populations
ATR1 A1166C
polymorphism
Tunisian South Indian13 Turkish14 Brazilian15
Patients
(n = 118)
Controls
(n = 150)
Patients
(n = 107)
Controls
(n = 114)
Patients
(n = 132)
Controls
(n = 100)
Patients
(n = 110)
Controls
(n = 104)
AA (%) 36.4 51.3 50.4 60.5 68.9 61.0 54.5 56.7
AC (%) 44.9 38.7 41.1 35.0 21.2 32.0 35.5 35.6
CC (%) 18.6 10 8.4 4.3 9.8 7.0 10.0 7.7
A allele (%) 58.9 70.7 66 78.1 79.5 77.0 72.3 74.5
C allele (%) 41.1 29.3 34 21.9 20.5 23.0 27.7 25.5
by guest on March 9, 2011jra.sagepub.comDownloaded from
Mehri et al. 5
are mediated by Ang II exerted through the activation of
specific high affinity receptors. The response to RAS acti-
vation depends on two factors: local Ang II concentration
and ATR1 density26 which can be modified by factors influ-
encing them. Recent studies revealed that the ATR1 density
is regulated in various tissues and cell types by a variety of
systemic factors, such as LDL-cholesterol, glucocorticoids,
hyperglycemia, or hyperinsulinemia, which have been
shown to upregulate ATR1, while Ang II, estrogen, and
proinflammatory cytokines downregulate ATR1.26 Ang II
activates nicotinamide adenine dinucleotide hydrogenase
(NADH)27 and induces oxidative stress by generating reac-
tive oxygen species (ROS)27 that may impair ventricular
microvascular blood flow causing myocardial ischemia,
cTnI-release, and ventricular dysfunction. ROS can rapidly
react with nitric oxide (NO), leading to peroxynitrite for-
mation, reduced NO availability, and endothelial dysfunc-
tion.27 Treatment with beta blockers and blockers of the
RAS system administered to patients long before entering
the study might have had an important protective role on
disease progression.28
Limitations of the study are that the number of patients
was small and there are no data in the literature with which
to compare the present results.
Conclusions
This study is the first to investigate the relationship between
an ATR1 polymorphism, serum ACE-activity and cTnI and
their effect on AMI. It indicates that the ATR1 CC genotype
is associated with an increased risk of developing an AMI.
Further investigations are needed to clarify the role of this
polymorphism and the possible mechanisms involved in
the phenomenon, such as modification of the number or
affinity of this receptor on accessible cells. It could be also
demonstrated that serum ACE activity and peak-cTnI lev-
els are strong predictors of an AMI. A larger study is
required to provide further evidence.
Table 4. Clinical and biological characteristics of the AMI patients according to ATR1 A1166C genotypes
Variables
CC
n = 22
AC
n = 53
AA
n = 43 p
Age (years) 62.9±8.9 62.8±13.2 60.7±11.7 0.657
Sex (male/female) 11/11 29/24 27/16 0.566
BMI (kg/m2) 26.0±5.0 28.1±5.8 28.6±4.9 0.171
Smokers, n16 31 34 0.087
Fasting glucose (mmol/L) 6.3±1.5 6.1±1.5 6.5±1.5 0.321
Diabetes, n12 21 24 0.233
HbA1c (%) 7.8±2.9 7.5±2.4 7.4±2.8 0.825
Hypertension, n8 29 26 0.177
DBP (mmHg) 97.5±18.3 94.7±15.6 90.2±14.1 0.361
SBP (mmHg) 159.2±28.3 152.0±21.6 146.0±19.8 0.080
Dyslipidemia, n8 10 6 0.098
Total cholesterol (mmol/L) 8.6±1.5 7.9±1.4 8.2±1.8 0.209
HDL-C (mmol/L) 2.0±0.1 1.9±0.2 1.9±0.3 0.358
LDL-C (mmol/L) 6.3±1.3 5.6±1.4 5.9±1.7 0.267
Triglycerides (mmol/L)a2 (1.95- 2) 2 (1.8- 2.1) 2 (1.8-2.3) 0.032
Peak cTnI (ng/ml) 46.8±3.1 42.7±5.5 41.2±6.7 0.001
Serum ACE activity (U/L) 123.3±34.4 103.0±31.3 82.5±29.0 0.000
aExpressed as median (IR); BMI: body mass index, SBP: systolic blood pressure; DBP: diastolic blood pressure; HDL: high-density lipoprotein; LDL:
low-density lipoprotein.
Figure 1. Distributions of serum angiotensin-converting
enzyme (ACE) activity and peak cardiac troponin I (cTnI) in
acute myocardial infarction patients with regards to the ATR1
A1166C genotypes.
by guest on March 9, 2011jra.sagepub.comDownloaded from
6 Journal of the Renin-Angiotensin-Aldosterone System XX(X)
Funding
This work was supported by a grant from Ministère de
l’Enseignement Supérieur, de la Recherche Scientifique et de la
Technologie UR03/ES08, Nutrition Humaine et Désordres
Métaboliques and Direction Générale de la Recherche Scientifique
et Technologique DGRST-USCR Spectrométrie de masse.
Conflict of interest statement
None declared.
References
1. Jaffe AS, Babuin L and Apple FS. Biomarkers in acute car-
diac disease. J Am Coll Cardiol 2006; 48: 1–11.
2. Mezzano SA, Ruiz-Ortega M and Egido J. Angiotensin II
and renal fibrosis. Hypertension 2001; 38: 635–638.
3. Millan MA, Kiss A and Aguilera G. Developmental changes
in brain angiotensin II receptors in the rat. Peptides 1991; 12:
723–737.
4. Kuizinga MC, Smits JF, Arends JW and Daemen MJAP.
AT2 receptor blockade reduces cardiac interstitial cell DNA
synthesis and cardiac function after rat myocardial infarc-
tion. J Mol Cell Cardiol 1998; 30: 425–434.
5. Paxton WC, Runge M, Horaist C, Cohen C, Alexander RW,
et al. Immunohistochemical localization of rat angiotensin II
at 1 receptor. Am J Physiol 1993; 264: 989–995.
6. Krieger EM and Santos RAS. Angiotensinas: Aspectos fisi-
ológicos. Hipertensão 1998; 1: 7-10.
7. Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru A,
Clauser E, et al. Angiotensin II type 1 receptor gene poly-
morphisms in human essential hypertension. Hypertension
1994; 24: 63–69.
8. Tiret L, Bonnardeaux A, Poirier O, Ricard S, Marques-Vidal
P, Evans A, et al. Synergistic effects of angiotensinconvert-
ing enzyme and angiotensin-II type 1 receptor gene poly-
morphisms on risk of myocardial infarction. Lancet 1994;
344: 910–913.
9. Smaoui M, Hammami S, Chaaba R, Attia N, Hamda KB,
Masmoudi AS, et al. Lipids and lipoprotein (a) concentration
in Tunisian type 2 diabetic patients relationship to glycaemic
control and coronary heart disease. J Diabetes Complicat
2004; 18: 258–263.
10. Bénéteau-Burnat B and Baudin B. Angiotensin-converting
enzyme: clinical applications and laboratory investigations
on serum and other biological fluids. Crit Rev Clin Lab Sci
1991; 28: 337–356.
11. Baudin B, Bénéteau-Burnat B, Crayon B and Giboudeau J.
Automated kinetic assay of angiotensin-converting enzyme
on Synchron CX-4. Clin Chem Enzym Comms 1995; 7:
41–48.
12. Hingorani AD and Brown MJ. A simple molecular assay for
the C1166 variant of the angiotensin II type 1 receptor gene.
Biochem Biophys Res Commun 1995; 213: 725–729.
13. Pullareddy BR, Srikanth Babu BMV, Karunakar KV,
Yasovanthi J, Kumar PS, Sharath A, et al. Angiotensin II
type 1 receptor gene polymorphism in myocardial infarc-
tion patients. J Renin Angiotensin Aldosterone Syst 2009; 10:
174–178.
14. Ulgen MS, Ozturk O, Yazici M, Kayrak M, Alan S, Koç F,
et al. Association between A/C1166 gene polymorphism of
the angiotensin II type 1 receptor and biventricular functions
in patients with acute myocardial infarction. Circ J 2006; 70:
1275–1279.
15. Araújo MA, Menezes BS, Lourenço C, Cordeiro ER, Gatti
RR and Goulart LR. The A1166C polymorphism of the angi-
otensin II type-1 receptor in acute myocardial infarction. Arq
Bras Cardiol 2004; 83: 409–413.
16. Canavy I, Henry M, Morange PE, Tiret L, Poirier O, Ebagosti
A, et al. Genetic polymorphisms and coronary artery disease
in the south of France. Thromb Haemost 2000; 83: 212–216.
17. Berge KE, Bakken A, Bohn M, Erikssen J and Berg K. A
DNA polymorphism at the angiotensin II type 1 receptor
(ATR1) locus and myocardial infarction. Clin Genet 1997;
52: 71–76.
18. Ranjith N, Pegoraro RJ, Rom L, Lanning PA and Naidoo
DP. Renin-angiotensin system and associated gene poly-
morphisms in myocardial infarction in young South African
Indians. Cardiovasc J S Afr 2004; 15: 22–26.
19. Jones A, Dhamrait SS, Payne JR, Hawe E, Li P, Toor IS, et al.
Genetic variants of angiotensin II receptors and cardiovascu-
lar risk in hypertension. Hypertension 2003; 42: 500–506.
20. Buraczyńska M, Pijanowski Z, Spasiewicz D, Nowicka T,
Sodolski T, Widomska-Czekajska T, et al. Renin-angiotensin
system gene polymorphisms: assessment of the risk of coro-
nary heart disease. Kardiol Pol 2003; 58: 1–9.
21. Takami S, Imai Y, Katsuya T, Ohkubo T, Tsuji I, Nagai K,
et al. Gene polymorphism of the renin-angiotensin system
associates with risk for lacunar infarction. The Ohasama
study. Am J Hypertens 2000; 13: 121–127.
22. Prasad P, Tiwari AK, Kumar KM, Ammini AC, Gupta A,
Gupta R, et al. Chronic renal insufficiency among Asian
Indians with type 2 diabetes: I. Role of RAAS gene poly-
morphisms. BMC Med Genet 2006; 7: 42–50.
23. Castellano M, Muiesan ML, Beschi M, Rizzoni D, Cinelli
A, Salvetti M, et al. Angiotensin II type 1 receptor A/C1166
polymorphism: Relationships with blood pressure and car-
diovascular structure. Hypertension 1996; 28: 1076–1080.
24. Pfeffer M. Enhancing cardiac protection after myocardial
infarction: rationale for newer clinical trials of angiotensin
receptor blockers. Am Heart J 2000; 139: S23–S28.
25. Mehri S, Baudin B, Mahjoub S, Zaroui A, Bénéteau-Burnat
B, Mechmeche R, et al. Angiotensin-converting enzyme
insertion/deletion gene polymorphism in a Tunisian healthy
and acute myocardial infarction population. Genet Test Mol
Biomarkers 2010; 14: 85–91.
26. Nickenig G and Harrison DG. The AT(1)-type angiotensin
receptor in oxidative stress and atherogenesis: Part II: AT(1)
receptor regulation. Circulation 2002; 105: 530–536.
27. Doughan AK, Harrison DG and Dikalov SI. Molecular
mechanisms of angiotensin II mediated mitochondrial
dysfunction. Linking mitochondrial oxidative damage
and vascular endothelial dysfunction. Circ Res 2008; 102:
488–496.
28. Komajda M, Jais JP, Reeves F, Goldfarb B, Bouhour JB,
Juillieres Y, et al. Factors predicting mortality in idiopathic
dilated cardiomyopathy. Eur Heart J 1990; 11: 824–831.
by guest on March 9, 2011jra.sagepub.comDownloaded from
... Tuy nhiên, cơ chế của NMCT vẫn còn chưa hoàn toàn sáng tỏ cho đến thời điểm hiện tại. Trong những thập niên qua, nhiều nghiên cứu phát hiện các biến thể gen có thể là dấu ấn tiềm năng liên quan với nguy cơ và tiên lượng của NMCT cấp [1], [2], [5], [7]. ...
... Ở châu Mỹ, Araujo MA và cs nhận thấy kiểu gen CC hiếm gặp nhất (10,0%) ở bệnh nhân Brazil NMCT cấp [1]. Ở châu Phi, các bệnh nhân Tunisia NMCT cấp có tỉ lệ kiểu gen CC thấp nhất (18,6%) [2]. Tuy nghiên, nghiên cứu của chúng tôi có tỉ lệ kiểu gen AA cao nhất. ...
... Tuy nghiên, nghiên cứu của chúng tôi có tỉ lệ kiểu gen AA cao nhất. Kết quả này cũng được ghi nhận trong hầu hết các nghiên cứu khác, trong khi nghiên cứu của Mehri S cho thấy kiểu gen AC có tỉ lệ cao nhất [2]. ...
Article
Mục tiêu: xác định tần suất kiểu gen của biến thể gen AGTR1 A1166C ở bệnh nhân nhồi máu cơ tim (NMCT) cấp. Đối tượng và phương pháp nghiên cứu: Đây là nghiên cứu cắt ngang, mô tả trên các bệnh nhân NMCT cấp tại Khoa Nội Tim Mạch và Khoa Tim Mạch Can Thiệp, Bệnh viện Chợ Rẫy từ 01/2020 đến 09/2020. Kiểu gen của biến thể AGTR1 A1166C được xét nghiệm bằng phản ứng chuỗi polymerase. Kết quả: Nghiên cứu có 305 bệnh nhân NMCT cấp lần đầu với tuổi trung bình 63,3 ± 11,9 và 69,5% bệnh nhân nam. Rối loạn lipid máu (89,8%) và tăng huyết áp (79,0%) là các yếu tố nguy cơ bệnh mạch vành thường gặp nhất. Nghiên cứu có 64,6% trường hợp NMCT cấp ST chênh lên và 76,7% độ I theo phân loại Killip. Tỉ lệ kiểu gen AA, AC và CC của biến thể AGTR1 A1166C lần lượt là 90,2%; 9,5% và 0,3%. Kết luận: Kiểu gen CC có tần suất thấp nhất trong biến thể gen AGTR1 A1166C của bệnh nhân NMCT cấp.
... For measuring serum ACE activity on the automated SYN-CHRON CX-4 DE (Beckman-Coulter) analyser with N-[3-(2-furylacryloyl]-L-phenylalanyl-L-glycyl-L-glycine (FAPGG) was used [17,18]. Serum ACE activity and cTn-I were measured as described previously [17,18]. ...
... For measuring serum ACE activity on the automated SYN-CHRON CX-4 DE (Beckman-Coulter) analyser with N-[3-(2-furylacryloyl]-L-phenylalanyl-L-glycyl-L-glycine (FAPGG) was used [17,18]. Serum ACE activity and cTn-I were measured as described previously [17,18]. cTn-I (ng/ml) was measured upon patient arrival and at 6, 12, 24, 48 and 96 h after reperfusion on the AxSYM analyzer (Abbott Laboratories, Abbott Park, IL, USA) using the three-step MEIA (Microparticle enzyme immunoassay). ...
... Control of blood pressure, lipid, and blood glucose levels is a proven strategy to reduce the risk of cardiovascular complications [22]. Both, diabetes and HTA, are independent predictors of mortality in AMI patients [17]. We found that the HbA1c, diastolic BP, and systolic BP were significantly higher in AMI patients compared to controls. ...
Article
Full-text available
The aim was to investigate this relationship by calculating 1) the correlation between peak troponin-C (peak-cTnI), levels of oxidative stress biomarkers, including lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CD)), and antioxidant enzyme activity (glutathione peroxidase (GPx)), and HbA1c and 2) the correlation between HbA1c and serum angiotensin-converting enzyme (ACE) activity, and its impact on the rate pressure product (RPP) in acute myocardial infarction (AMI). A case-control study was performed in 306 AMI patients having undergone coronary angiography and on 410 controls. GPx activity was reduced in association with increased MDA and CD in patients. Peak-cTnI was positively correlated with HbA1c, MDA, and CD levels. Serum ACE activity was negatively correlated with GPx. HbA1c was positively correlated with ACE activity and RPP. Linear regression analysis showed that peak-cTnI, ACE activity and HbA1c are significant predictors of AMI. Elevated HbA1c and peak-cTnI levels are associated with RPP elevation causing AMI. In conclusions, patients with elevated HbA1c, elevated ACE activity and cTnI are at increased risk of AMI with increasing RPP. Patients at risk of AMI can be identified at an early stage if the biomarkers HbA1c, ACE activity, and cTnI are measured and preventive measures are taken in a targeted manner.
... Many genetic markers associated with AMI have been identified, including genes encoding components of the renin-angiotensin-aldosterone system (RAAS). The AGTR1 gene encoding the angiotensin II type 1 receptor (AT1R) is located on the long arm of chromosome 3 (3q21- 25), and A1166C is the most studied polymorphism [4]. This gene variant is at the untranslated 3' region and has a base substitution of adenine with cytosine at nucleotide position 1166 of the mRNA sequence. ...
... The CC genotype was the least common (1.1%) in our study population. This feature is consistent with other studies on different races, not just on Asian populations [9,10,[23][24][25]. Our study showed that patients with the AC and CC genotypes had a higher rate of � LAD 90% stenosis than AA genotype carriers. ...
Article
Full-text available
The pathogenesis and prognosis of patients with acute myocardial infarction (AMI) may be influenced by both genetic and environmental factors. Findings on the relationship of polymorphisms in various genes encoding the renin-angiotensin-aldosterone system with coronary artery lesions and mortality in AMI patients are inconsistent. The aim of this study was to determine whether the AGTR1 A1166C genetic polymorphism affects coronary artery lesions and 1-year mortality in post-AMI patients. Patients with their first AMI admitted to Cho Ray Hospital, Vietnam, from January 2020 to August 2021 were enrolled in this prospective clinical study. All participants underwent invasive coronary angiography and were identified as having the genotypes of AGTR1 A1166C by way of a polymerase chain reaction method. All patients were followed up for all-cause mortality 12 months after AMI. The association of the AGTR1 A1166C polymorphism with coronary artery lesions and 1-year mortality was evaluated using logistic regression and Cox regression analysis, respectively. Five hundred and thirty-one AMI patients were recruited. The mean age was 63.9 ± 11.6 years, and 71.6% of the patients were male. There were no significant differences in the location and number of diseased coronary artery branches between the AA and AC+CC genotypes. The AC and CC genotypes were independently associated with ≥ 90% diameter stenosis of the left anterior descending (LAD) artery (odds ratio = 1.940; 95% confidence interval (CI): 1.059–3.552, p = 0.032). The 1-year all-cause mortality rate difference between patients with the AC and CC genotypes versus those with the AA genotype was not statistically significant (hazard ratio = 1.000, 95% CI: 0.429–2.328, p = 1.000). The AGTR1 A1166C genetic polymorphism is associated with very severe luminal stenosis of the LAD but not with mortality in AMI patients.
... It has been described a substitution of cytosine for adenine at position 1166 (A1166C) (rs5186) in the AT1R gene, and this variant has been associated with myocardial infarction [13]. Also, Mehri and coworkers established that A1166C is associated with Myocardial Infarction in Tunisian, [14] and Abdul-Hasan et al., in Iraqi populations [15]. ...
... We identified that A1166C represents a genetic risk factor por Myocardial Infartion in Mexican young individuals, and more important its remained as an independent risk factor for STEMI after adjustment with other risk factors such diabetes, hypertension, smoking, family history of CAD and dyslipidemia. Our results are in accordance with other investigators, whom reported a positive association between this genetic variant and Myocardial Infarction [14,15]. In a meta analysis realized by Zhang et al., demonstrated that A1166C genetic variant was associated with coronary heart disease [31]. ...
Article
Full-text available
Background Previous studies had identified genetic variants associated with Myocardial Infarction, but results are inconclusive. We examined the association between FII G20210A (rs1799963), FV G1691A (rs6025), FXIII 97G > T (rs11466016), ATR1 A1166C (rs5186) and MTHFR A1298C (rs1801131) polymorphisms and ST elevation Myocardial Infarction in young Mexican individuals. Methods We included a total of 350 patients with Myocardial Infarction <45 years old and 350 controls matched by age and gender. The polymorphisms were analyzed by PCR-RFLP using specific restriction enzymes. DNA fragments were separated by electrophoresis in 2% gel of agarose and visualized using SYBR green. Results The A1166C (p = 0.004) but not FXIII 97G > T (p = 0.19), G20210A (p = 0.32), G1691A (p = No significant) and A1298C (p = 0.21) polymorphisms were associated with increased risk for ST elevation Myocardial Infarction. Moreover, dyslipidemia, hypertension, smoking and family history of atherothrombotic disease were associated. Conclusions We found that A1166C represented increased risk for ST elevation Myocardial Infarction. However, G20210A, G1691A, 97G > T, and A1298C were not associated. In addition, we had determined that Glu298Asp, PLA1/A2, TAFI Thr325Ile, ACE I/D, AGT M235T and PAI-1 4G/5G polymorphisms represented increased risk in the same group of patients. However, MTHFR C677T, AGT T174M, FV G1691A, TSP-1 N700S, MTHFR C677T and TAFI 174 M polymorphisms were no associated. Our results suggest that in young patients with ST Myocardial Infarction, those polymorphisms could contribute to premature endothelial dysfunction, atherothrombosis, vasoconstriction, increased platelet aggregation, muscle cell migration and proliferation. Further studies are required to try to better assess gene-gene and gene-modifiable factors interaction.
... Biochemical measurements were carried out according to validated methods. Plasma glucose concentration was evaluated using an enzymatic kit (glucose oxidase, Randox, Antrim, UK), total cholesterol and triglycerides by enzymatic methods using Randox reagents and LDL and HDL cholesterol determined as described by Smaoui et al. [13] Serum ACE activity and troponin I (cTn-I) were determined as described previously [3,14]. ...
... cTnI is expressed only in cardiac muscle, which allows these biomarkers to achieve extremely high speci city or myocardial damage [24]. Con rming our present results, we previously showed in a Tunisian population that higher serum ACE activity and elevated peak-cTnI levels might be clinically useful as markers to assess risk for myocardial infarction [3,14]. Furthermore, we found that the glutathione peroxidase (GPx) was higher in healthy controls than NSTEMI patients. ...
Preprint
Full-text available
The hemodynamic determinants of myocardial oxygen demand measured were heart rate (HR), systolic blood pressure (BP), and rate pressure product (RPP). This study aimed to evaluate the impact of lipid profile, cardiac biomarkers, and serum angiotensin-converting enzyme (ACE) activity, oxidative stress (plasma malondialdehyde, MDA; conjugated diene, DC), and antioxidant status (glutathione peroxidase, GPx) on BP. Three hundred and six non-ST-elevated myocardial infarction (NSTEMI) patients compared to 410 healthy controls. The diastolic and systolic BP was correlated positively with serum ACE activity. The rate pressure product (RPP) was correlated negatively with Fasting glucose (r= -0.144; p = 0.012), HbA1c (r= -0.117; p = 0.041) and GPx activity (r= -0.148; p = 0.009), and positively with smoking (r = 0,197; p = 0.001), BMI (r = 0,219; p = 0.001), peak cTnI (r = 0.131; p = 0.022), serum ACE activity (r = 0,190; p = 0.001) and DC level (r = 0.189; p = 0.001) in NSTEMI patients. Regarding healthy controls, no correlation was found between the diastolic or systolic BP with serum ACE activity, peak cTnI, MDA, DC level, GPx activity, and lipid parameters. The existence of a specific correlation between the rate pressure product, diastolic and systolic BP and, lipid profile, serum ACE activity and, cardiac biomarkers, oxidative stress, and antioxidant status increase the NSTEMI risk on patients.
... CAD is a multifactorial disease triggered by environmental as well as genetic factors [3]. Not only smoking, diabetes mellitus, obesity, hypertension, and low-density lipoprotein (LDL) increases the risk of CAD, but also genetic susceptibility plays a role. ...
Article
Full-text available
Coronary artery disease (CAD) is a multifactorial disease that involves genetic and environmental interaction. In addition to the well-known CAD risk factors, such as diabetes mellitus, hypertension, hyperlipidemia, and atherosclerosis, it has a genetic component that predisposes to its occurrence even in young people. One of the most commonly studied genes that increase the susceptibility to CAD is renin-angiotensin system (RAS) genes polymorphisms mainly angiotensin-converting enzyme gene (ACE) polymorphisms, angiotensinogen polymorphisms, angiotensin- II type 1 receptor gene polymorphisms, and many other genes. These genetic polymorphisms have a direct association with CAD development or indirect association through causing atherosclerosis and hypertension which, in turn, are complicated by CAD later on. The difference between genetic mutations and polymorphisms lies in the frequency of the abnormal genotype. If the frequency is 1% and more in the general population, it is called polymorphism and if it is less than 1%, then it is called a mutation. According to our findings, after thorough searching, which support the association of RAS genes polymorphisms with premature CAD, hypertension, hypertrophic cardiomyopathy, and atherosclerosis, we recommend additional studies in the form of clinical trials and meta-analyses aiming to create a specific diagnostic tool for CAD risk assessment and discovering the high-risk people as early as possible. Targeted gene therapy, being the future of medicine, needs to be taken into researchers' consideration. It can have promising results in these cases.
Article
Введение: Изучение полиморфизмов генов, ответственных за развитие артериальной гипертензии является многообещающим направлением медицины. Артериальная гипертензия является мультифакторным заболеванием, которое зависит от образа жизни, окружающей среды и питания, а также полиморфизмов генов. Полиморфизмы генов ренин – ангиотензин – альдостероновой системы играют немаловажную роль в патогенезе артериальной гипертензии. Цель: обзор литературных источников по молекулярно-генетической основе развития артериальной гипертензии. Материалы и методы: Поиск источников проводился в базах PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), Scopus(https://www.scopus.com/), Ebscohost(https://search.ebscohost.com/), Medline(https://www.nlm.nih.gov/), The Сocrane Library (http://www.cochranelibrary.com/), SpringerLink(https://link.springer.com/), Web of Knowledge (Thomson Reuters)(https://login.webofknowledge.com), Параграф Медицина (https://prg.kz/medicine_info), ScienceDirect (https://www.sciencedirect.com/). Глубина поиска составила 15 лет: с 2002 по 2017 годы. Критериями включения являлись: отчеты о рандомизированных и когортных исследованиях, проведенных на больших популяциях; мета-анализы и систематические обзоры; статьи на английском, русском и казахском языках. Критериями исключения явились: статьи, описывающие единичные случаи и серии случаев; статьи, опубликованные ранее 2002 года; материалы, не имеющие доказательной базы, резюме докладов, тезисы и газетные статьи. Из найденных 90 литературных источника, 55 были отобраны в качестве аналитического материала для данной статьи. Результаты: Обзор источников показал, что исследования последних лет, которые посвящены изучению полиморфизмов генов при артериальной гипертензии дают разные результаты в разных популяциях. Выводы: Оценка роли полиморфных вариантов генов на риск развития артериальной гипертензии в разных популяциях является актуальной и требующей дальнейшего изучения. Introduction: The study of polymorphisms of genes responsible for the development of arterial hypertension is a promising direction of medicine. Hypertension is a multifactorial disease that depends on lifestyle, environment and nutrition, as well as polymorphisms of genes. Polymorphisms of the genes of the renin - angiotensin - aldosterone system play an important role in the pathogenesis of hypertension. The aim: A review of the literature on the molecular genetic basis of the development of hypertension. Materials and methods: Literature search was conducted in the databases PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), Scopus (https://www.scopus.com/), Ebscohost (https://search.ebscohost.com/), Medline (https://www.nlm.nih.gov/), The Сocrane Library (http://www.cochranelibrary.com/), SpringerLink (https://link.springer.com/), Web of Knowledge (Thomson Reuters) (https://login.webofknowledge.com), Paragraph Medicine (https://prg.kz/medicine_info), ScienceDirect (https://www.sciencedirect.com/). The depth of the search was 15 years: from 2002 to 2017. The inclusion criteria were: reports on randomized and cohort studies conducted on large populations; Meta-analyzes and systematic reviews; Articles in English, Russian and Kazakh. Criteria for exclusion were: articles describing single cases and a series of cases; Articles published earlier in 2002; Materials that do not have an evidence base, summaries of reports, abstracts and newspaper articles. Out of 90 literary sources, 55 were selected as analytical material for this article. Results: A review of the sources showed that studies of recent years that are devoted to the study of polymorphisms of genes in arterial hypertension give different results in different populations. Conclusions: Evaluation of the role of polymorphic variants of genes on the risk of developing arterial hypertension in different populations is topical and requires further study. Кіріспе: Артериялық гипертензия дамуына жауапты гендер полиморфизмдерін зерттеу медицинаның көп үміт күтерлік бағытына жатады. Артериялық гипертензия өмірсүру салтына, қоршаған ортаға және тамақтануға, сонымен қатар гендер полиморфизміне тәуелді мультифакторлы ауру. Ренин–ангиотензин–альдостерон жүйесінің гендер полиморфизмдері артериялық гипертензия патогенезінде айтарлықтай маңызды рөл атқарады. Мақсаты: артериялық гипертензия дамуының молекулярлы – генетикалық негіздерібойынша әдебиеттерді іздестіру. Іздеу стратегиясы: Әдебиеттердііздестіру PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), Scopus (https://www.scopus.com/), Ebscohost (https://search.ebscohost.com/), Medline (https://www.nlm.nih.gov/), The Сocrane Library (http://www.cochranelibrary.com/), SpringerLink (https://link.springer.com/), Web of Knowledge (Thomson Reuters) (https://login.webofknowledge.com), Параграф Медицина (https://prg.kz/medicine_info), ScienceDirect (https://www.sciencedirect.com/) базаларында жүргізілді. Іздестіру тереңдігі 15 жылды құрады: 2002 мен 2017 жылдар аралығында жүргізілді. Әдебиетті қосу критерийлері: үлкенпопуляцияларда жүргізілген, рандомизирленген мен когортты зерттеулер туралы есептер; ағылшын, орыс және қазақ тілдеріндегі мақалалар. Қосымша осы тақырыптағы мақалалардың жүйелі шолулар мен мета – анализдері кіргізілді. Әдебиеттікіргізбеу критерийлеріне жатты: жеке оқиғамен оқиғалар сериясын сипаттаған мақалалар, 2002 жылдан бұрын шыққан мақалалар, дәлелі базасы жоқ материалдар, баяндамалардың резюмелері, тезистер және газет мақалалары. 90 әдебиеттік қайнардан55 мақала осы мақаланың анализдік материалы ретінде алынды. Нәтижелері: Мақалаларды шолу барысы артериялық гипертензия кезінде гендер полиморфизмдерін зерттеуге арналған соңғы жылдардағы зерттеулер әртүрлі популяцияларда әртүрлі нәтижелерді береді. Қорытынды: Әртүрліпопуляциядағы артериялық гипертензиядаму қаупінде гендердің полиморфты варианттарының рөлін бағалау өзекті және әрі қарай зерттеуді қажет етеді.
Article
Full-text available
Введение: Изучение полиморфизмов генов, ответственных за развитие артериальной гипертензии является многообещающим направлением медицины. Артериальная гипертензия является мультифакторным заболеванием, которое зависит от образа жизни, окружающей среды и питания, а также полиморфизмов генов. Полиморфизмы генов ренин – ангиотензин – альдостероновой системы играют немаловажную роль в патогенезе артериальной гипертензии. Цель: обзор литературных источников по молекулярно-генетической основе развития артериальной гипертензии. Материалы и методы: Поиск источников проводился в базах PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), Scopus (https://www.scopus.com/), Ebscohost (https://search.ebscohost.com/), Medline (https://www.nlm.nih.gov/), The Сocrane Library (http://www.cochranelibrary.com/), SpringerLink (https://link.springer.com/), Web of Knowledge (Thomson Reuters) (https://login.webofknowledge.com), Параграф Медицина (https://prg.kz/medicine_info), ScienceDirect (https://www.sciencedirect.com/). Глубина поиска составила 15 лет: с 2002 по 2017 годы. Критериями включения являлись: отчеты о рандомизированных и когортных исследованиях, проведенных на больших популяциях; метаанализы и систематические обзоры; статьи на английском, русском и казахском языках. Критериями исключения явились: статьи, описывающие единичные случаи и серии случаев; статьи, опубликованные ранее 2002 года; материалы, не имеющие доказательной базы, резюме докладов, тезисы и газетные статьи. Из найденных 90 литературных источника, 55 были отобраны в качестве аналитического материала для данной статьи. Результаты: Обзор источников показал, что исследования последних лет, которые посвящены изучению полиморфизмов генов при артериальной гипертензии дают разные результаты в разных популяциях. Выводы: Оценка роли полиморфных вариантов генов на риск развития артериальной гипертензии в разных популяциях является актуальной и требующей дальнейшего изучения
Article
Full-text available
Coronary artery disease (CAD) and myocardial infarction (MI) have reached epidemic levels in the Arab world. The well-recognized familial clustering of CAD implies that genetics plays a key role in its development. Several CAD/MI genetic association studies have been conducted, but the outcomes have been inconsistent. In this study, we aimed to systematically review and quantitatively summarize the current evidence on genetic polymorphisms associated with CAD/MI risk in the Arab world. We systematically searched five literature databases (Science Direct, PubMed, Scopus, EMBASE, and Web of Science). We included all genetic polymorphisms with odds ratio (OR) 1 that were significantly associated with CAD/MI risk among Arabs. Review Manager software v5.02 was used to conduct the meta-analysis. Publication bias was measured using Begg’s funnel plot and Egger’s test based on STATA software v15.1. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the association. I2-statistic was used to assess heterogeneity. In total, 75 studies comprising 36,125 cases and 31,730 controls were included, and 62 studies were eligible for meta-analysis. A total of 80 captured variants within or near 59 genes were found to be associated with an increased CAD/MI susceptibility. We performed 46 individual meta-analyses tests for 46 variants. The pooled OR of association with CAD/MI ranged from 1.14 to 7.57, with a median (interquartile range) of 1.83 (1.64 – 2.57). With the few studies published so far, there appears to be a unique genetic and clinical susceptibility profile for Arab patients with CAD/MI. The findings of this study will pave the way to perform future genetic association studies that will help identify potential therapeutic targets against CAD/MI.
Article
Full-text available
The role of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) on acute myocardial infarction (AMI) is controversial. To assess the effect of the ACE I/D polymorphism on AMI compared with the healthy controls and its relationship with serum ACE activity in a Tunisian population. A total of 119 patients with AMI were compared with 238 healthy controls from the same geographical area. ACE genotyping was determined by polymerase chain reaction, and serum ACE activity was measured with N-[3-(2-furylacryloyl]-L-phenylalanyl-L-glycyl-L-glycine as substrate. The ACE I/D polymorphism was significantly different between patients and controls (p < 0.0001). The frequencies of the DD genotype and the D allele were statistically higher in patients with AMI as compared with the controls and were associated with increased risk of AMI (DD vs. ID and II: odds ratio = 4.27, p < 0.0001, 95% confidence interval = 2.65-6.86; D vs. I: odds ratio = 3.15, p < 0.0001, 95% confidence interval = 2.26-4.40). This association was independent of other cardiovascular risk factors but dyslipidemia (p = 0.002) that was not represented in AMI patients with II genotype and in a lower extent with hypertension (p < 0.05). Serum ACE activity was significantly higher in AMI patients with ACE DD genotype compared with the subjects with ID or II genotype (p = 0.034) and was not correlated with other cardiovascular risk factors. ACE DD genotype associated with higher serum ACE activity is increased in the studied population and might be clinically useful as markers to assess risk for AMI.
Article
Full-text available
Acute myocardial infarction is commonly known as heart attack. It is a multifactorial disease influenced by environmental and genetic factors.The objective of the present study was to investigate the association of the angiotensin II type 1 receptor gene A/C polymorphism in South Indian myocardial infarction patients.Subjects and methods. The present study included a total number of 221 subjects (107 myocardial infarction patients and 114 age- and sex-matched controls). Demographic and clinical characteristics were collected. Lipid profiles were estimated. DNA was isolated and the angiotensin II type 1 receptor gene A/C polymorphism was determined by polymerase chain reaction. Comparison of the lipid profiles between patients and controls showed that patients had statistically highly significant values (p=0.0001).The CC genotype of the angiotensin II type 1 receptor was not associated with myocardial infarction patients when compared to controls. CC vs. AA was chi(2) = 2.08, odds ratio 2.30, 95% confidence interval 0.72 - 7.23, and p value was 0.14. The angiotensin II type 1 receptor CC genotype is not a risk factor for myocardial infarction in patients in a South Indian population.
Article
Full-text available
RESUMO OBJETIVO:Avaliar a associação do polimorfismo A1166C do gene do receptor AT1 da angiotensina II (AT1R) com o infarto agudo do miocárdio e a severidade da doença arterial coronariana. MÉTODOS: Estudo prospectivo, transversal de 110 pacientes com infarto agudo do miocárdio submetidos à angiografia coronariana com lesão significante (> 50%) avaliada por três critérios de severidade: número de vasos lesados, morfologia da placa aterosclerótica e escore de risco coronariano. Sem lesões coronarianas 104 indivíduos controles. O polimorfismo A1166C do gene do AT1R foi determinado pela reação em cadeia da polimerase no DNA dos leucócitos do sangue periférico. Os fatores de risco coronariano clássicos foram analisados em todos os indivíduos. RESULTADOS: Na estratificação dos genótipos em relação aos fatores de risco apenas o tabagismo teve predominância nos heterozigotos AC (p = 0,02). A freqüência dos genótipos nos pacientes infartados foi de AA = 54,5%; AC = 35,5% e CC = 10%, sendo similar e não significativa em relação aos controles (p = 0,83). Não houve aumento do risco de infarto agudo do miocárdio nas comparações dos genótipos CC vs AA (OR = 1,35; IC-95% = 0,50 - 3,59), AC vs AA (OR = 1,03; IC-95% = 0,58 - 1,84 e AA+AC vs AA (OR = 1,33; IC-95% = 0,51 - 3,45). Nenhum dos critérios de severidade teve associação significativa com os genótipos. CONCLUSÃO: Os nossos resultados indicam não haver associação do polimorfismo A1166C do AT1R com o infarto agudo do miocárdio e nem com a severidade da doença arterial coronariana segundo nossos resultados.
Article
The objective of the study was to investigate the involvement of angiotensin II receptor subtypes 1 and 2 in total interstitial cell and endothelial cell DNA synthesis and cardiac function after myocardial infarction (MI) in the rat. Rats with a MI were treated with either AT1 receptor antagonist GR138950C (2 mg/kg/day) or the AT2 receptor antagonist PD123319 (3 mg/kg/day). Total interstitial cell (that is endothelial cells and fibroblast-like cells) DNA synthesis in the interventricular septum was significantly increased 2 weeks after MI. 33+/-3% of DNA synthesizing cells were identified as endothelial cells. PD123319, but not GR138950C significantly reduced total interstitial DNA synthesis. Both agents did not alter the fraction of DNA synthesizing endothelial cells. The effects on cardiac function were studied in parallel groups. MI reduced both cardiac output and stroke volume at 3 weeks after MI PD123319 reduced CO, whereas GR138950C did not affect cardiac function. Thus, the data show that AT2 receptor blockade, but not AT1 receptor blockade early after rat myocardial infarction inhibits interstitial DNA synthesis and decreases cardiac function.
Article
The polymorphism of the angiotensin-converting enzyme gene is considered to be associated with increased risk for stroke, but there is a diversity in the results obtained. The genetic involvement of the renin-angiotensin system in stroke also remains unclear. To predict the genetic risk of lacunar infarction, we conducted an association study in an Ohasama population, which is the cohort in a rural region of northern Japan. A total of 134 subjects without major neurological, cardiovascular, or metabolic disorders were recruited. Using brain magnetic resonance imaging, the number of lacunae in each of four brain regions were calculated, and periventricular hyperintensity was classified into five grades. We used the following four candidate gene polymorphisms: angiotensin converting enzyme (ACE)/Insertion(I)-Deletion(D), angiotensinogen (AGT)/M235T, angiotensin II type 1 receptor (AT1)/A1166C, type 2 receptor (AT2)/C3123A, to examine the association between polymorphisms and the severity of lacunar infarction. AGT/M235T was significantly associated with the number of lacunae in the brain stem, the basal ganglia (P .05), and whole brain (P< .005) regions. The AT1 polymorphism was also significantly associated with the number of lacunae in the basal ganglia and whole brain regions (P< .05), and with periventricular hyperintensity grade (P< .005) in the younger population. However, ACE and AT2 polymorphisms failed to show an association with either the number of lacunae or the PVH grade. We concluded that AGT and AT1 polymorphisms are independent genetic risk factors for lacunar infarction.
Article
A study of factors predicting mortality was performed in 69 patients with idiopathic dilated cardiomyopathy by analyzing 14 parameters according to clinical, electrocardiographic and echocardiographic findings. On admission 64% of the patients were in NYHA functional class 3 or 4. During a mean follow-up period of 18 months 43 patients died; 31 of refractory heart failure and 12 suddenly. 1 year survival was 58%. Multivariate analysis (Cox model) revealed that the independent predictors for mortality due to refractory heart failure were left ventricular enddiastolic diameter, NYHA functional class and systolic blood pressure; the presence of tricuspid regurgitation predicted mortality due to sudden death.
Article
Angiotensin I-converting enzyme (ACE) is a peptidyldipeptide hydrolase that is located mainly on the luminal surface of vascular endothelial cells but also in cells derived from the monocyte-macrophage system. Physiologically, ACE is a key enzyme in the renin-angiotensin system, converting angiotensin I into the potent vasopressor angiotensin II and also inactivating the vasodilator bradykinin. Increased serum ACE activity (SACE) has been reported in pathologies involving a stimulation of the monocytic cell line, primarily granulomatous diseases. Sarcoidosis is the most frequent and the better studied of these diseases; high SACE is not only a well-established marker for the diagnosis but is also a useful tool for following its course and evaluating the effect of therapy. SACE can also be increased in nonsarcoidotic pulmonary granulomatous diseases such as silicosis and asbestosis, in extrathoracic granulomatous pathologies such as Gauchers disease and leprosis, and, to a lesser extent, in nongranulomatous disorders such as hyperthyroidism or cholestasis. On the other hand, monitoring sarcoidosis obviates the measurement of ACE activity in other biological fluids, e.g., broncho-alveolar and cerebrospinal fluids, in the search of a locoregional dissemination or dis-simulation of the disease. Decreased SACE has been reported in vascular pathologies involving an endothelial abnormality, e.g., deep vein thrombosis, and in endothelium dysfunctions related to the toxicity of chemo- and radiotherapy used in cancers, leukemias, and hematopoietic or organ transplantations. SACE is also of interest for monitoring arterial hypertension treated with specific synthetic ACE inhibitors. These various reasons for determining ACE activity have led to the development of numerous methods. The most widely used is the spectrophotometric assay using hippuryl-histidyl-leucine as substrate. Fluorimetric and radiochemical assays using both classic and novel substrates have been proposed, but they are time consuming, require special apparatus, and are not suited to automation. Kinetic spectrophotometry of furylacryloyl-phenylalanyl-glycyl-glycine hydrolysis is now used extensively because it is easy to automatize. Efforts are now required to standardize one or more of these assays. Indeed, "normal" plasma values differ not only according to the substrate, but also to the method of determination and to sex and age.
Article
AII binding and distribution were measured in rat brain during development by autoradiographic techniques using radioiodinated [Sar1,Ile8]AII. At all ages, from 2 days to 7 weeks, binding was present in the circumventricular organs, and areas related to pituitary hormone secretion and modulation of sympathetic activity. At early stages of development, AII binding was transiently expressed in a number of motor- and sensory-related areas. These findings support a role for AII in the control of water intake and autonomic activity at all stages of development, and suggest that the peptide may be involved in the maturation of neuronal function during development.
Article
A study of factors predicting mortality was performed in 201 patients with dilated cardiomyopathy (163 men, 38 women, mean age: 48±11 years) by multivariate analysis (Cox Model) of 51 clinical, electrocardio-graphic, echocardiographic and haemodynamic parameters, 56 patients died during follow-up (mean follow-up: 57.1 ± 29.9 months). 5 year survival was 77 ±3%. The following parameters were independent predictors of mortality: first symptom: pulmonary oedema, peripheral oedema, syncope; duration of symptoms at the time of inclusion; end systolic left ventricular volume; end diastolic left ventricular diameter; pulmonary artery systolic pressure; and their combination had the most accurate predictive value for death. A quantitative score (s) was calculated and used to define three subgroups: A: s ≤4.5; B: 4.5<s<6; C: s ≥6. Five-year survival was 90 ±5% in group A; 84± 4% in B and only 53 ± 7% in C. In conclusion, overall survival was good in this population of all stage dilated cardiomyopathy; factors related to clinical severity, left ventricular dilation, systolic pulmonary artery pressure and duration of symptoms defined a subgroup of patients with poor prognosis.