Promoter polymorphism of Promoter polymorphism of macrophage Migration Inhibitormacrophage Migration Inhibitoryy Factor (MIF) gene in Czech and Factor (MIF) gene in Czech and

Russian patients with myocardial Russian patients with myocardial infarctioninfarction

  Petrkova J1,2,Tereshchenko IP3, Lukl J2, Mrazek F2, Voevoda MI3,

Petrek M2

1Laboratory of Immunogenomics, Palacky University; 2Dept. of Internal Medicine I, Faculty Hospital Olomouc, Czech republic

3Inst. of Internal Medicine, RAMS Novosibirsk, Russian Federation

This work was supported by Czech government (ME-856). I.T. is recipient of Visegrad fund fellowship)

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

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

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)

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

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

219patients with MI

137unrelated

healthy

controls

240patients with MI

174unrelated

healthy

controls

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.

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 1st

MI episode) was found.

• The proportion of MIF rs1007888 GG homozy-gotes was higher among Czech female patients compared with female control group (Figure)

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)

MIF -173 G/CCzech population (N=356) Russian population (N=414)

MI (N=219)

Controls(N=137)

MI(N=240)

Controls(N=174)

Genotype%

GG 74.4 75.2 68.3 72.4

GC 21.5 22.6 30.4 24.1

CC 4.1 2.2 1.3 3.4

Alleles%

G 85.2 86.5 83.5 84.5

C 14.8 13.5 16.5 15.5

C 25.6 24.8 31.7 27.6

p (genotypes): CZ, 0.61, RU, 0.14; p (alleles): CZ, 0.60, RU, 0.72; p (carriage): CZ, 0.87, RU, 0.37.

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)

0,344

0,149

0,000

0,050

0,100

0,150

0,200

0,250

0,300

0,350

0,400

female patients female controls

p females = 0.027 ; p males = 0.157

0,256

0,171

0,000

0,050

0,100

0,150

0,200

0,250

0,300

male patients male controls

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.