Chemokine RANTES –403 G/A polymorphism in two Slavonic populations with myocardial infarction Tereshchenko IP 1,2, Petrkova J 2,3, Mrazek F 2, Navratilova Z 2, Lukl J 3, Voevoda MI 1, Petrek M 2 1 Institute of Internal Medicine, RAMS Novosibirsk, Russia; 2 Immunogenetics and 3 Internal Medicine I, Palacky University Olomouc, Czech Republic (The study was supported by Czech government (ME-856). I.T. is recipient of Visegrad fund fellowship)

Atherosclerosis & Inflammation & Genetics Inflammation of coronary artery wall is a critical process in the pathogenesis of myocardial infarction (MI). MI is thought to have important genetic component. The chemokine RANTES/CCL5 activates and attracts T-lymphocytes to the sites of ongoing inflammation. RANTES gene is a candidate for MI susceptibility.

RANTES variants & Myocardial Infarction A single nucleotide polymorphism SNP locates at the position -403 of the RANTES gene promoter (Guanin by Adenin -403 G→A) RANTES-403*A allele tended to associate with a higher risk of coronary artery disease (CAD) in Hungarian patients (Szalai et al. Atherosclerosis 2001;158:233-39). In a LURIC (The Ludwigshafen Risk and Cardiovascular health) study in German population RANTES 403*A allele was significantly associated with CAD (Simeoni et al. European Heart Journal 2004; 25, )

AIMS To investigate whether RANTES promoter -403 G→A polymorphism is associated with myocardial infarction in the two Caucasian population (Czech, West- Slavonic; Russian, East-Slavonic) In this case-control study to replicate the Hungarian and German studies in other populations.

Study population Diagnosis of myocardial infarction was made according to standard international criteria. (Eur Heart J. 2000;21:1502) Slavonic population West-Slavonic Czech 224 patients with MI 140 unrelated healthy controls East-Slavonic Russian 244 patients with MI 197 unrelated healthy controls

RANTES promoter polymorphism genotyping and statistical analysis RANTES -403 G/A polymorphism was genotyped by polymerase chain reaction with sequence specific primers (PCR-SSP) Statistic:A statistical calculations were performed using the SPSS v.13.0 (SPSS Inc, Chicago, IL) The distribution of the RANTES genotypes and alleles were analyzed using the Pearson’s 2x2 contingency table  2 -test and odds ratios and 95% confidence interval (CI) were estimated. The control populations was tested for conformity to the Hardy-Weinberg equilibrium.

RESULTS There were no significant differences in RANTES -403 G/A genotype, allelic and phenotype (carriage) frequencies between MI patients and controls for both populations (Table 1) No differences after subgroup analysis (male / female and age at 1 st MI episode) was found. The proportion of RANTES-403*A allele was similar in control groups across several Caucasian populations (Figure 1)

Table 1: Genotype, allele and phenotype (carriage rates) frequencies of the RANTES -403 G/A polymorphism in the groups of patients with myocardial infarction and control subjects (in two investigated population) RANTES -403 G/A Czech population (N=364)Russian population(N=441) MI (N=224) Control (N=140) MI (N=244) Control (N=197) Genotype % GG GA AA a a Alleles % G A b b A allele carriage % A c c a p value for genotype: Czech – 0.75, Russian – 0.48; b p value for alleles: Czech – 0.49, Russian – 0.27; c p value for A allele carriage: Czech – 0.45, Russian – 0.46.

Figure 1: Proportions of RANTES -403*A allele in patient with coronary artery disease and control groups across selected populations Czech republic, Olomouc; Russian Federation (RF), Novosibirsk: myocardial infarction, data of present study. Germany:coronary atherosclerosis, Simeoni et al.,Eur Heart J.,2004;25:1438. Hungary:coronary atherosclerosis, Szalai et al., Atherosclerosis.2001;158:233.

DISCUSSION The population size of Hungary cohort (Szalai et al,2001) and our investigated two Slavonic population was identical. However, genotype and alleles frequencies RANTES G-403*A distributed not equally between two populations. Distribution of genotypes in LURIC study deviated significantly from the expected in Hardy-Weinberg equilibrium. In this study were performed statistical tests that do not assume HWE and RANTES -403*A allele was significantly associated with CAD (Simeoni et al., 2004). Our estimated groups are limits for the numbers of participants but populations were strong compliance with the HWE. Thus, technical genotyping errors are not the cause for present discrepancies. Our pilot study, performed in cases and controls of Slavonic ethnic origin, did not confirm this findings.

CONCLUSION The data do not support association between RANTES -403*A allele and MI as reported from LURIC (LUdwigshafen Risk and Cardiovascular health) and Hungarian cohort At least in Slavonic population, RANTES promoter -403 G/A polymorphism does not contribute to genetic determination of MI.