Contribution of the TGFB1 Gene to Myocardial Infarction Susceptibility.

Carriage frequencies of alleles and genotypes of theTGFB1 gene polymorphous loci -509C>T (rs1800469), 869T>C (rs1982073), 915G>C (rs1800471), which affect the level of cytokine TGF-ß1 production, were analyzed in the patients of Russian ethnic descent with myocardial infarction (MI) (406 cases) and in the control group of the same ethnic descent (198 controls). Significant association with MI was observed in carriage frequencies of the alleleTGFB1*-509T (p=0.046, OR =1.45, 95% CI: 1.02-2.06), genotypes TGFB1*869T/T (p=0.0024, OR =1.75, 95% CI: 1.22-2.51), andTGFB1*915G/G (p=0.048, OR=1.76, 95% CI: 1.05-2.97). Linkage disequilibrium analysis for these SNPs has shown that the associations revealed can be considered to be independent. A complex analysis of MI association with combinations of alleles/genotypes of said SNPs indicates their cumulative effect. An analysis of susceptibility to early-onset MI (≤ 50 years old) revealed a positive association of the alleleTGFB1*-509T (p=0.002, OR=2.24, 95% CI: 1.35-3.71) and genotypeTGFB1*869T/T (p=0.008, OR=1.93, 95% CI: 1.18-3.15), as well as their additivity. An analysis of susceptibility to recurrent MI revealed an association of the genotypeTGFB1*-509T/T (p=0.0078, OR=2.60, 95% CI: 1.28-5.28). The results obtained indicate the important role of theTGFB1gene in susceptibility to MI, including early-onset and recurrent MI, in Russians.

[Value of allele gene polymorphism of the inflammation system for prognosis of patients with myocardial infarction].

In recent years levels of a number of inflammatory markers namely C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF) etc. are measured for the purpose of postinfarction risk evaluation. Dynamics of inflammatory markers concentrations can reflect processes occurring in atherosclerotic plaque and coronary arteries. Concentrations of inflammatory markers depend particularly on genetic factors affecting transcription levels of individual genes. This data suggest that genotypes which determine increased inflammatory markers levels in blood can increase risk of unfavorable events after myocardial infarction. STUDY PURPOSES: Analysis of influence of allelic polymorphisms C1444T of CRP gene (rs1130864), G(-174)A of IL6 gene (rs1800795), A(-308)G of TNF gene (rs1800629), G252A of LTA gene (rs909253), (-509) of TGFB1 gene (rsl800469) and delta32 (w/d) of CCR5 gene (rs333) on development of cardiac unfavorable events in Russian patients with MI during two years follow-up. 211 Russian patients were included (52.3+/-10.3 years), 160 men (50.1+/-10.6 years) and 51 women (55.2+/-10.1 years). After two years of follow-up patients were examined in hospital, or telephon call occurred for determination of patient's condition or end point assessment. The end points were cardiac death, recurrent MI, recurrent hospitalization with unstable angina or stroke, CABG or PTCA performing. The genotyping was performed by methods based on polymerase chain reaction (PCR): PCR-SSP and PCR-RFLP. Analysis revealed association of allele T (p=0.036, OR=1.6, 95%CI: 1.052.6) and of allele T carriage (genotypes CT+TT) (p=0.046, OR=1.9, 95%CI: 1.053.6) of polymorphism C1444T of CRP gene with unfavorable events development. Analysis of survival rate by Kaplan-Meier estimation showed that cumulative part of patients without unfavorable events was significantly lower among allele T carriers than among carriers of genotype C/C of polymorphism C1444T CRP. Allele A of polymorphism A252G of LTA gene was also associated with unfavorable events risk (p=0.034, OR=1.96, 95%CI: 1.073.06). There was no association of polymorphisms delta 32 (w/d) of CCR5 gene, A(-308)G of TNF gene, G(-174)C of IL-6 gene, C(-509)T of TGFB1 gene with unfavorable events development.

[Polymorphic variants of genes encoding interleukin-6 and fibrinogen, the risk of ischemic stroke and fibrinogen levels].

Carriage frequencies of alleles and genotypes of polymorphous locus of -174G>C IL6 (rs1800795) were analyzed in the patients with ischemic stroke (IS) of Russian ethnic descent (200 cases) and in the control group of the same ethnic descent with similar sex and age (140 controls). Significant differences were identified in frequencies of carriage (in homo- or heterozygous form) of allele IL6*-174G (p = 0.0029, OR = 2.9, 95% CI: 1.4-5.8), which can be considered as risk factor for IS and in frequencies of IL6*-174C/C genotype carriage, correspondingly (p = 0.0029, OR = 0.35, 95% CI: 0.17-0.69). After sex stratification of patients and controls similar significant differences were observed only between female patients and controls, after age stratification the difference was observed only for the age group older 60 years. Complex analysis of association of SNP -174G>C IL6 alleles and genotypes carriage in combination with SNP 4266A>G (Thr312Ala) FGA (rs6050) (see symbol) -249C>T FGB (rs1800788) with IS revealed protective combinations IL6*-174C/C + FGA* 4266A (see symbol) IL6*-174C/C + FGB*-249C, which were slightly more significant than single protective genotype IL6*-174C/C associated with IS and their ORs didn't differ substantially from the single genotypes's OR value. At the same time the combinations of alternative allele IL6*-174G with the same FGB*-249C or FGA* 4266A alleles were revealed and their association significance levels as well as OR values were lower than the values for the single risk allele IL6*-174G. In case of the mutual carriage of IL6*-174G allele with FGA*4266A/A, FGB*-249C/C genotypes or with combinations of these alleles/genotypes the "neutralized" effect became stronger. In other words, we observed association of IS with allele/genotype combinations of genes IL6, FGA and FGB, in which IL6 plays key role and FGA and FGB have modulating function. In analysis of association of fibrinogen plasma levels with three analyzed polymorphous loci significant differences were not revealed.

[Polymorphism C1444T of C-reactive protein gene and C-reactive protein concentration in blood serum of healthy people and patients with myocardial infarction].

UNLABELLED: CRP level is a risk factor of development of ischemic heart disease (IHD) and acute myocardial infarction (MI) in healthy people, while in patients with cardiovascular diseases it is a marker of unfavorable prognosis. It has been shown in recent investigations that individual variations of plasma CRP levels to a great extent are genetically determined. These data constitute a basis for the study of associations of polymorphic variants of the CRP gene with risk of MI in healthy people as well as with unfavorable prognosis in IHD patients. MATERIAL AND METHODS: We included into the study 232 Russian patients aged 52.3 +/- 10.3 years, 175 men (50.1 +/- 10.6 years) and 57 women (55.2 +/- 10.1 years). Control group comprised 159 Russians without history of cardiovascular diseases and other serious severe concomitant diseases (age 60.5 +/- 14 years), 76 men (age 57.3 +/- 13.9 years ) and 83 women (age 63.1 +/- 14 years). CRP concentration was measured initially (at the moment of hospitalization), on days 3, at discharge, in 1 and 6 months, 1 year after onset of infarction. For genomic typing of C1444T polymorphism of CRP gene we used restriction fragment length analysis of products of polymerase chain reaction (PCR). RESULTS: Distribution of genotypes of C1444T polymorphism of CRP gene: C/C 51.8%, C/T 35.8%, T/T 12.4% in patients with MI; C/C 55.2%, C/T 40.2%, T/T 4.6% in control group. We found significant difference (p = 0.006, relative risk [RR] 0.3, 95% confidence interval [CI] 0.15-0.74) in frequency of carriers of C1444 allele (sum of C/C and C/T genotypes), which was higher in control group. Correspondingly in the group of patients with MI T/T genotype was met significantly more frequently than in control (p = 0.006, RR 3.0, 95% CI 1.3-6.5), and can be looked upon as risk factor of MI. We found no relation between carriage of CRP alleles/genotypes of CRP and one year prognosis in patients with MI. Analysis of association of the C1444T polymorphism with CRP concentration revealed significant relationship between T/T genotype and higher CRP level.

[Complex analsis of association of inflammation genes with myocardial infarction].

Carriage frequencies of alleles and genotypes of functionally important polymorphous loci of some inflammation genes: proinflammatory cytokines genes IL-6, LTA and TNF, anti-inflammatory cytokine gene TGFB1 and CC chemokine receptor 5 gene CCR5 were analyzed in the patients with myocardial infarction (MI) of Russian ethnic descent (199 cases) and in the control group of the same ethnic descent (142 controls). Complex analysis using APSampler algorithm revealed MI association with carriage of all polymorphous variants studied, as individual risk factors (insertion/deletion polymorphism of CCR5 and SNP G252A LTA) or only in combination with other alleles/genotypes. Carriage of bi- or triallelic combinations was associated with MI more significantly than carriage of any their subsets: single alleles or allele pairs. Protective triallelic combination d*CCR5 + 252G*LTA(+) -174C*Ll-6 was found to be most significant (p = 0.0006, OR = 0.23, CI = 0.090-0.56). Separate analysis of genetic susceptibility to MI for men and women displayed sexual dimorphism for CCR5 gene.