1. Promoter polymorphism of macrophage Migration Inhibitory Factor (MIF) gene in Czech and Russian patients with myocardial infarction Promoter polymorphism of macrophage Migration Inhibitory Factor (MIF) gene in Czech and Russian patients with myocardial infarction Petrkova J 1,2,Tereshchenko IP 3, Lukl J 2, Mrazek F 2, Voevoda MI 3, Petrek M 2 1 Laboratory of Immunogenomics, Palacky University; 2 Dept. of Internal Medicine I, Faculty Hospital Olomouc, Czech republic 3 Inst. of Internal Medicine, RAMS Novosibirsk, Russian Federation This work was supported by Czech government (ME-856). I.T. is recipient of Visegrad fund fellowship)

2. Atherosclerosis & Inflammation Cytokine genetic variability Inflammation of coronary artery wall is a critical process in the pathogenesis of myocardial infarction (MI). Cytokines, namely proinflammatory, are implicated in atherosclerosis and pathogenesis of MI Genes encoding for cytokines are polymorphic: some functional variants affect cytokine production Cytokine polymorphism may be associated with MI susceptibility and/or manifestation

3. Macrophage Migration Inhibitory Factor Cytokine with pleiotropic functions Key regulator of inflammatory immune response Expressed in macrophages, cardiomyocytes, vascular smooth muscle cells etc. Regulates production of proinflammatory cytokines

4. MIF: candiate molecule in atherosclerosis MIF was detected in early and advanced atherosclerotic lesions MIF levels are increased in circulation of patients with acute myocardial infarction Animal studies support role for MIF in pathogenesis of vascular disease MIF gene (chr. 22q11.2) is polymorphic, with a functional SNP in promotor and further candidate SNPs (e.g. in 3´- flanking region)

5. AIMS To investigate whether polymorphism in MIF gene promotor (-173 G/C) is associated with myocardial infarction in two Caucasian populations (Czech, Russian) To explore if this polymorphism modifies manifestation of myocardial infarction To study a role of another MIF single nucleotide polymorphism (rs1007888) in MI susceptibility

6. Study population Diagnosis of myocardial infarction was made according to standard international criteria. (Eur Heart J. 2000;21:1502) Slavonic population West-Slavonic Czech East-Slavonic Russian 219 patients with MI 137 unrelated healthy controls 240 patients with MI 174 unrelated healthy controls

7. MIF polymorphism genotyping and statistical analysis MIF -173 G/C (rs 755622) and MIF rs1007888 polymorphism were genotyped by polymerase chain reaction with sequence specific primers (PCR-SSP) Statistic: Statistical calculations were performed using the SPSS v.13.0 (SPSS Inc, Chicago, IL) The distribution of 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.

8. RESULTS There were no significant differences in MIF - 173 G/C genotype, allelic and phenotype (carriage) frequencies between MI patients and controls for both populations (Table) Regarding MIF-173 SNP, no differences after subgroup analysis (male / female) and age at 1 st MI episode) was found. The proportion of MIF rs1007888 GG homozy- gotes was higher among Czech female patients compared with female control group (Figure)

9. Table: Genotype, allele and phenotype (carriage rates) frequencies of the MIF -173 G/C polymorphism in the groups of patients with myocardial infarction and control subjects (in two investigated population) p (genotypes): CZ, 0.61, RU, 0.14; p (alleles): CZ, 0.60, RU, 0.72; p (carriage): CZ, 0.87, RU, 0.37.

10. Figure 1: Proportions of MIF rs1007888 GG homozygotes in Czech patients with myocardial infarction and Czech control subjects in females (upper left) and males (bottom right) p females = 0.027 ; p males = 0.157

11. CONCLUSION The data from two-population study do not support association between MIF-173 G/C polymorphism and susceptibility to / manifestation of myocardial infarction at least in Slavonic Caucasians. A relationship between MIF SNP rs1007888 and MI described for Czech females should be further explored.