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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
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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:
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DOI: 10.1177/1470320310391833
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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
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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
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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)
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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
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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.
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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.
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