Abstract
Coronary artery inflammation is a critical process in the pathogenesis of myocardial infarction (MI). The chemokine CCL5/RANTES (regulated upon activation, normal T cells expressed and secreted) is expressed in advanced atherosclerotic lesions. Functional polymorphisms of the RANTES gene can, therefore, be involved in the pathogenesis of coronary artery disease. We examined the association of polymorphisms in the RANTES gene with myocardial infarction in Slavonic populations of Czech and Russian origin. A total of 467 post-MI patients and 337 control subjects were genotyped for RANTES promoter G-403A (rs2107538) and intron 1.1 T/C (rs2280789) variants by PCR-SSP. Both RANTES genotypes and allele frequencies did not differ between case and control groups. Haplotype-based analysis also failed to reveal an association between MI and investigated markers. Strong linkage disequilibrium was detected between particular RANTES alleles. The data do not support an association between RANTES G-403A polymorphism and MI, as reported previously.
Go to: 1. Introduction
Atherosclerosis is a pathological process that takes place in the major arteries and represents one of the causes of myocardial infarction (MI), ischemic stroke, and peripheral artery disease. Atherosclerosis, a multifactorial condition determined by environmental as well as genetic factors, has a strong inflammatory component [
1] characterised by deregulation of gene expression in macrophages within atherosclerotic plaques, together with local overproduction of cytokines. Among those, chemokines (chemotactic cytokines) have also been implicated in atherosclerosis on the basis of clinical studies and animal disease models [
2].
The chemokine RANTES, also known as CC chemokine ligand (CCL5), is involved in the activation and proliferation of T-lymphocytes and is considered as a major chemokine implicated in both the acute and chronic phases of inflammation. Tissue RANTES expression is differentially regulated: in atherosclerosis, RANTES mRNA has been detected in the lymphocytes, macrophages, myofibroblasts, and endothelial cells of human arteries undergoing accelerated atherosclerosis but not in normal coronary arteries [
3]. RANTES was also found deposited on activated endothelium or murine atherosclerotic carotid arteries [
4]. Platelets, which are also implicated in the atherosclerotic process including myocardial infarction (MI), are known to store RANTES in intracellular granules in the basal state and to secrete it when stimulated with thrombin [
5].
Single nucleotide polymorphisms in the RANTES gene promoter and intronic region have been described: C-28G, G-403A (relative to transcription start site), polymorphism in intron 1 (In1.1 T/C), and in the 3′untranslated regions [
6,
7]. The case-control study investigating RANTES SNP G-403A in Germans associated this SNP with a susceptibility to coronary atherosclerosis [
8]; in another study, in Hungarians, however, this association was not significant [
9]. That RANTES polymorphisms may play a role in cardiac pathology was also suggested by a report enrolling patients with type 2 diabetes mellitus and end stage renal disease [
10]: the carriage of either RANTES -403 G/A or intronic polymorphism (In1.1 T/C) was associated with all-cause mortality due mainly to cardiac events.
Concerning the effect of these SNPs on RANTES expression, an increased gene expression was linked with the minor allele in the RANTES gene at the nucleotide position -403 and -28 [
11,
12]. However,
in vitro functional data are more important for RANTES intronic polymorphism T/C: In1.1C allele or haplotypes that include this variant showed a strong dominant association with rapid progression to AIDS [
7]. Furthermore, RANTES gene polymorphisms were associated with the outcomes of HCV and HBV infections [
13,
14]. By analogy, atherosclerotic lesions, the underlying cause of coronary artery disease (CAD) and MI, represent a series of highly specific cellular and molecular events of the inflammatory response [
1]. Despite convincing evidence for a role of the RANTES polymorphisms in different inflammatory diseases, their role in CAD requires further investigation.
Given the inflammatory component of coronary atherosclerosis and the lack of case-control investigations of more than one RANTES polymorphism in MI, this study examined the relationship between two RANTES polymorphisms (promoter G-403A, intron1.1 T/C) with their haplotypes and myocardial infarction. In agreement with genetic epidemiology principles, our "replication" study comprised two population cohorts (Czech, Russian) differing in ethnicity from those populations in which the RANTES gene was investigated previously (Hungarian, German).
Go to: 2. Materials and Methods
2.1. Study Population
A total of 804 unrelated Caucasian individuals were enrolled into this case-control study, of which 467 were MI cases and 337 healthy controls subjects. Two population groups were recruited: (1) Czech (Olomouc) with 223 MI patients and 140 control subjects and (2) Russian (Novosibirsk) with 244 cases and 197 controls from the MONICA project register.
Table 1 shows demographic and clinical characteristics of the study groups.