CC chemokine receptor (CCR)2 polymorphism in Czech patients with myocardial infarction.
ABSTRACT Examining an association between myocardial infarction (MI) and the Val/Ile polymorphism in the gene for CC chemokine receptor (CCR)2 at the position 64 (CCR2-V64I), 122 MI Czech patients and 277 unrelated control (C) subjects were genotyped by PCR-SSP. The frequency of the VI genotype of CCR2-V64I was increased in MI patients in comparison with the control population (P=0.03). Further analysis revealed that relationship between the VI genotype and MI is specific only for females and, strikingly, this genotype was associated to an early MI onset (before or at the age of 50 years). Females with the VI genotype were seven times more prone to suffer from MI before 50 years than those with the VV genotype (P<0.01). If the VI genotype of the CCR2-V64I is indeed a risk factor for an earlier MI onset in females must be checked by independent studies in other centres and/or populations.
- SourceAvailable from: Rory R Koenen
Article: Touch of chemokines.[show abstract] [hide abstract]
ABSTRACT: Chemoattractant cytokines or chemokines constitute a family of structurally related proteins found in vertebrates, bacteria, or viruses. So far, 48 chemokine genes have been identified in humans, which bind to around 20 chemokine receptors. These receptors belong to the seven transmembrane G-protein-coupled receptor family. Chemokines and their receptors were originally studied for their role in cellular trafficking of leukocytes during inflammation and immune surveillance. It is now known that they exert different functions under physiological conditions such as homeostasis, development, tissue repair, and angiogenesis but also under pathological disorders including tumorigenesis, cancer metastasis, inflammatory, and autoimmune diseases. Physicochemical properties of chemokines and chemokine receptors confer the ability to homo- and hetero-oligomerize. Many efforts are currently performed in establishing new therapeutically compounds able to target the chemokine/chemokine receptor system. In this review, we are interested in the role of chemokines in inflammatory disease and leukocyte trafficking with a focus on vascular inflammatory diseases, the operating synergism, and the emerging therapeutic approaches of chemokines.Frontiers in Immunology 01/2012; 3:175.
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ABSTRACT: Coronary artery disease (CAD) was the second leading cause of death during the last 3 years in Taiwan. Smooth muscle cells, monocytes/macrophages, and endothelial cells produce monocyte chemoattractant protein-1 (MCP-1) within atherosclerotic plaques following binding to the chemokine receptor-2 (CCR-2). Previous studies have well-documented the association between MCP-1 expression and susceptibility to, or clinicopathological features, of CAD. This study investigated the relationships between MCP-1-2518A/G and CCR-2-V64I genetic polymorphisms and CAD in the Taiwanese population. A total of 608 subjects, including 392 non-CAD controls and 216 patients with CAD, were recruited and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to evaluate the effects of these two polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR = 1.629; 95 % CI = 1.003-2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006-2.270), had a higher risk of CAD as compared with AA genotypes. Results also revealed that subjects with at least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD. G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p < 0.05). In conclusion, MCP-1-2518G and CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518G could be through effects on atrial fibrillation in CAD patients.Molecular Biology Reports 07/2012; 39(9):9023-30. · 2.51 Impact Factor
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ABSTRACT: Inflammatory mechanisms are important in stroke risk, and genetic variations in components of the inflammatory response have been implicated as risk factors for stroke. We tested the inflammatory gene polymorphisms and their association with ischemic stroke in a Chinese Han population. A total of 1,124 ischemic stroke cases and 1,163 controls were genotyped with inflammatory panel strips containing 51 selected inflammatory gene polymorphisms from 35 candidate genes. We tested the genotype-stroke association with logistic regression model. We found two single nucleotide polymorphisms (SNPs) in CCL11 were associated with ischemic stroke. After adjusting for multiple testing using false discovery rate (FDR) with a 0.20 cut-off point, CCL11 rs4795895 remained statistically significant. We further stratified the study population by their hypertension status. In the hypertensive group, CCR2 rs1799864, CCR5 rs1799987 and CCL11 rs4795895 were nominally associated with increased risk of stroke. In the non-hypertensive group, CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 and CCL11 rs4795895 were associated with ischemic stroke. After correction for multiple testing, CCR2 rs1799864 and CCR5 rs1799987 remained significant in the hypertensive group, and CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 remained significant in the non-hypertensive group. Our results indicate that inflammatory genetic variants are associated with increased risk of ischemic stroke in a Chinese Han population, particularly in non-hypertensive individuals.Journal of Neuroinflammation 07/2012; 9:162. · 4.35 Impact Factor
CC chemokine receptor (CCR)2 polymorphism in Czech patients
with myocardial infarction?
Jana Petrkovaa,b, Zuzana Cermakovaa,c, Jiri Drabeka, Jan Luklb, Martin Petreka,*
aDepartment of Immunology, Palacky ´ University, I.P. Pavlova str. 6, Olomouc, Czech Republic
bDepartment of Internal Medicine I, Palacky ´ University, Olomouc, Czech Republic
cBlood Centre, Faculty Hospital, Ostrava, Czech Republic
Received 3 March 2003; accepted 6 March 2003
Examining an association between myocardial infarction (MI) and the Val/Ile polymorphism in the gene for CC chemokine
receptor (CCR)2 at the position 64 (CCR2-V64I), 122 MI Czech patients and 277 unrelated control (C) subjects were genotyped by
PCR-SSP. The frequency of the VI genotype of CCR2-V64I was increased in MI patients in comparison with the control population
(P?/0.03). Further analysis revealed that relationship between the VI genotype and MI is specific only for females and, strikingly,
this genotype was associated to an early MI onset (before or at the age of 50 years). Females with the VI genotype were seven times
more prone to suffer from MI before 50 years than those with the VV genotype (P B/0.01). If the VI genotype of the CCR2-V64I is
indeed a risk factor for an earlier MI onset in females must be checked by independent studies in other centres and/or populations.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: CCR2-V64I; Coronary artery disease; Atherosclerosis
Atherosclerotic inflammation of coronary arteries is a
critical process in the pathogenesis of myocardial
infarction (MI). Initial phase of atherosclerosis is
characterised by migration of monocytes into the vessel
wall mediated by chemotactic cytokines such as MCP-1
(CCL2)  and fractalkine (CX3CL1) . Effects of
these chemokine ligands are mediated via receptor
molecules: CC chemokine receptor (CCR)2, binding
MCP-1, and CX3C chemokine receptor (CX3CR)1, the
fractalkine receptor. Both aforementioned receptors are
encoded by polymorphic genes. A role for CX3CR1 and
its polymorphism in atherosclerosis has been implicated
from animal  and human  data. By contrast, a
plausible relevance of the MCP-1 receptor for ather-
ogenesis, based on the observation of alleviation of
atherosclerotic process in CCR2? //? / mice , has not
yet been confirmed in humans. We have, therefore,
focused on CCR2 gene and investigated whether a single
nucleotide polymorphism (SNP) CCR2-V64I is asso-
ciated with coronary artery disease manifested as MI.
Into a case control, association study we enrolled 122
patients (96 males, 26 females) presenting with MI and
277 age-matched control, healthy subjects (174 males,
103 females). All patients and control subjects were of
Czech (Caucasian) origin; cardiovascular symptomatol-
ogy in control subjects was excluded by questionnaire.
Informed consent was obtained both from our patients
and control subjects. The criteria for diagnosis of MI
were compatible with those recommended by an inter-
national consensus . Genotyping for CCR2-V64I
polymorphism was performed by PCR with sequence
specific primers as previously described . Significance
of differences between genotype and gene (allelic)
frequencies of the polymorphism in patient and control
groups was assessed by standard 2?/2 x2analysis by
SIGTEST, a computer-based program that uses a Woolf?/
Haldane correction in cases of small numbers.
The distribution of genotype and gene frequencies of
CCR2-V64I polymorphism in Czech patients with MI
and control subjects is shown in Table 1. The control
?Part of this work was presented at the Annual Congress of the
British Society for Immunology, Harrogate, 4th?/7th December 2001.
* Corresponding author. Tel.: ? /420-58-844-2285; fax: ? /420-58-
E-mail address: email@example.com (M. Petrek).
Immunology Letters 88 (2003) 53?/55
0165-2478/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
population was in Hardy?/Weinberg equilibrium with
regard to the distribution of CCR2 genotypes. The
frequency of the VI genotype of CCR2-V64I was
increased in MI patients in comparison with the control
population; patients with the VI genotype were in
increased risk of MI (odds ratio, OR 1.7; 95% con-
fidence interval, CI 1.1?/2.8; P?/0.03). To further
characterise this genotype as a plausible risk factor for
MI, we have explored if the association between MI and
the VI genotype of CCR2-V64I is present also in patient
subsets: first, the probands were subdivided according to
their sex and, second according to the age when their
first MI symptoms appeared (Table 2). Strikingly, the
VI genotype was related to the disease only in female
patients while in males this genotype was not associated
with MI (P?/0.19); in females the P value was equal to
0.05 and, therefore, we interpret it as a link between MI
and the VI genotype rather than an association, despite
that the OR value reached 2.5. Interestingly, further
analysis revealed that association of the VI genotype
with MI is significantly restricted to those female
patients, who presented with the first MI episode before
or at the age of 50 years. While in patients with the later
MI manifestation (after 50 years) CCR2-V64I genotype
frequencies resembled those in the control population,
the distribution of genotypes in patients with an earlier
onset of MI (at or before 50 years) differed substantially
from the remaining two groups (Table 2, bottom lines).
Among this subgroup of female patients with an early
MI onset, VI was the prevailing genotype (Fig. 1).
Females with the VI genotype were seven times more
prone to suffer from MI before 50 years than those with
the VV genotype (OR 7.2, 95% CI 1.7?/30.0, PB/0.01).
The comparison of the VI genotype frequencies between
the two groups of female patients, i.e. between those
suffering from MI before and after the age of 50 years,
confirmed that the VI genotype may modulate the age of
MI onset: the OR exceeded the value of 5.0, the
difference however fell just short off significance due
to low patients number (P?/0.06).
This is a first report of association of CCR2-V64I
polymorphism with coronary artery disease, and speci-
fically with an early manifestation of MI in females.
However, our study is not the first investigation of
CCR2 polymorphism in this disease condition. Re-
cently, genetic variation at the chemokine receptors
CCR5 and CCR2 was explored in Spanish patients with
Occurrence of genotypes and alleles of the CCR2-V64I polymorphism in Czech control population and Czech patients with MI
Study group GenotypeAllele
Genotype and allelic frequencies are given in parentheses.
aPatients vs. controls, P?/0.028 (OR, 1.70; 95% CI, 1.06?/2.75).
bPatients vs. controls, P?/0.054.
Distribution of genotypes of CCR2-V64I polymorphism in Czech
control and patient population after subdivision according to sex and
the age when the patients suffered from the first MI
Sex Groups and subgroups Genotype
Male Patients (n?/96)
134 (77.0%) 40 (23.0%)
29 (30.2%)a0 (0%)
Female Patients (n?/26)
Female Patients MI B/50 years 3 (37.5%)
Patients MI ?/50 years 14 (77.8%)
Genotype frequencies are given in parentheses.
aMale patients vs. male controls, P?/0.187.
bFemale patients vs. female controls, P?/0.054.
cFemale patients with MI B/50 years vs. female controls, P?/0.007
(OR, 7.18; 95% CI, 1.72?/30.04).
Fig. 1. Frequency (in percentage) of the VI genotype of CCR2-V64I
polymorphism in Czech control female population and in female
patients with MI after age of 50 years compared to the VI genotype
frequency in females with first MI before or at the age of 50 years.
MIB/50 yr vs. Control, P B/0.01, MIB/50 yr vs. MI?/50 yr, P?/0.06,
MI?/50 yr vs. Control, P?/0.57.
J. Petrkova et al. / Immunology Letters 88 (2003) 53?/55
MI . This study assigned a protective role against
early MI to CCR5D32 mutation but association of
CCR2-V64I polymorphism with MI was not observed
. Another study, directed at six different polymorph-
isms of the chemokine system in Hungarian population,
also did not implicate CCR2-V64I polymorphism in
coronary artery disease. By contrast, the authors basing
on under-representation of CCR2-64 II homozygous
individuals among patients speculated about a protec-
tive effect of I allele against MI . However, only male
probands were enrolled into the Spanish case-control
study  and there is no data on proportion of females
in the Hungarian patient group . Further, the study in
Hungarians did not accounted for the age of presenta-
tion of MI . Non-inclusion of the specific subset of
female patients with early MI, in which we report an
increase of the VI genotype, is indeed a major reason for
the discrepant interpretation of the results of our and
the other [7,8] studies. Confounding due to distinct
ethnic origin of investigated populations is not likely
because the CCR2-V64I allelic and genotype frequencies
in healthy controls from all three investigated popula-
tions were similar; e.g., for the VI genotype, Czechia
20.9%, Spain 19.0%  and Hungary 21.3% . Also, the
diagnostic criteria for inclusion into the study did not
substantially differ with the only exception that propor-
tion of our patients, who in addition to standard criteria
underwent coronary angiography, was higher than in
the group of Spanish patients.
Although this study was conducted in accordance
with the guidelines for proper performance of associa-
tion studies, including careful characterisation of clinical
phenotype [9,10], it has some limitations. The signifi-
cance of our observations could be strengthened if we
recruited more female patients, however we were limited
by less frequent occurrence of MI in females. We are
also aware that there are many more candidate SNPs in
the CCR2 gene or that the functional importance of the
polymorphism selected for this study has not been yet
clarified. However, for this initial investigation of
chemokine polymorphism in coronary artery disease
we decided to limit ourselves to CCR2-V64I because of
the existence of inter-relationship between this and other
SNPs in the region, standardised methodology  and
mainly because of the fact that the data published so far
were controversial and limited only to male population
From geneticist point of view, coronary artery disease
is a complex disease, in which the interactions between
many genes are complemented by environmental and
intrinsic factors . Therefore, the mechanisms by which
CCR2-V64I SNP may contribute to an earlier manifes-
tation of coronary atherosclerosis in females remain at
the level of speculations. Our main reason for reporting
the observed association between the VI genotype of
CCR2-V64I polymorphism and early MI in Czech
females already at this stage of investigations is to
invoke replication of our results in another centres and/
or populations. This would be in accordance not only
with proper practice for genetic association studies but
also with current opinion on their interpretation [10,11].
This work was supported by the Grant agency of the
Czech Ministry of Health (IGA MZCR NI/7308-3);
partial support was obtained from a Czech government
fund (MSMT151100002). Technical assistance of Ms A.
Vevodova and M. Lukesova is gratefully acknowledged.
 T.J. Reape, P.H.E. Groot, Atherosclerosis 147 (1999) 213?/225.
 P. Lesnik, C.A. Haskell, I.F. Charo, J. Clin. Invest. 111 (2003)
 D.H. McDermott, J.P.J. Halcox, W.H. Schenke, M.A. Waclawiw,
M.N. Merrell, N. Epstein, A.A. Quyyumi, P.M. Murphy, Circ.
Res. 89 (2001) 401?/407.
 W. Peters, I.F. Charo, Curr. Opin. Lipidol. 12 (2001) 175?/180.
 European Society of Cardiology/American College of Cardiology,
Eur. Heart J. 21 (2000) 1502?/1513.
 M. Petrek, J. Drabek, V. Kolek, J. Zlamal, K.I. Welsh, M. Bunce,
E. Weigl, R.M. du Bois, Am. J. Respir. Crit. Care Med. 162
 P. Gonzalez, R. Alvarez, A. Batalla, J.R. Reguero, V. Alvarez, A.
Astudillo, G.I. Cubero, A. Cortina, E. Coto, Genes Immun. 2
 C. Szalai, J. Duba, Z. Prohaszka, A. Kalina, T. Szabo, B. Nagy,
L. Horvath, A. Csaszar, Atherosclerosis 158 (2001) 233?/239.
 N.B. Zak, S. Shifman, A. Shalom, A. Darvasi, IMAJ 4 (2002)
 E.K. Silverman, L.J. Palmer, Am. J. Respir. Cell Mol. Biol. 22
 Editorial, Lancet 361 (2003) 357.
J. Petrkova et al. / Immunology Letters 88 (2003) 53?/55