[The analysis of association between type 2 diabetes and polymorphic markers in the CDKAL1 gene and in the HHEX/IDE locus].

The increase in diabetes was noted at the turn of the 21st century. Patients with type 2 diabetes (T2DM) make up the majority of patients. Diabetes is a multifactorial disease. It arises from adverse effects of environmental factors on the body of genetically susceptible peoples. According to modern concepts, T2DM is a polygenic disease. Each of the involved genes contributes to the risk of developing of this disease. In our study, the association between polymorphic genetic markers rs7756992, rs9465871, rs7754840, and rs10946398 in the CDKAL1 gene and rs1111875 in the HHEX/IDE locus and T2DM in the Russian population were studied. Four hundred forty patients with type 2 diabetes and 264 healthy individuals without any signs of the disease were examined. The comparative analysis of distribution of genotypes and allele frequencies points to an association between polymorphic genetic markers rs7756992, rs9465871, and rs10946398 in the CDKAL1 gene and this disease. For the other polymorphic genetic markers (rs7754840 in the CDKAL1 gene and rs1111875 in the HHEX/IDE locus), no statistically significant associations are found. On the basis of these data, we can conclude that the CDKAL1 gene is associated with development of T2DM. For the HHEX/IDE locus, such an association is absent.

[Association of the polymorphisms of the FTO, KCNJ11, SLC30A8 and CDKN2B genes with type 2 diabetes].

To study the association with diabetes mellitus type 2 we performed anal- ysis of the distribution of frequencies of alleles and genotypes of polymorphic markers of FTO, KCNJ11, SIC30A8 and CDKN2B genes. The study included groups of T2DM patients and unrelated controls of Russian origin. Analysis of the distribution of frequencies of alleles and genotypes of the polymorphic markers of KCNJ11, SLC30A8 and CDKN2B genes showed the presence of association with T2DM in Russian population, while for the FTO gene was not found statistically significant associations with type 2 diabetes. We can conclude that in Russian population main role in the development of type 2 diabetes play genes, affecting the level of syn- thesis and secretion of the insulin in beta-cells of the pancreas.

[Prognostic value of levels of brain natriuretic peptide and genetic factors in patients after acute coronary syndrome].

Prognostication of the course of disease in patients with high risk of unfavorable outcome of ischemic heart disease (IHD) is of great importance for creation of individualized strategy of treatment. We have investigated contribution of levels of brain natriuretic peptide (BNP) and genetic factors in the risk of development of complications of atherosclerosis in patients who have had acute coronary syndrome. We started to follow 324 patients on day 10 of stable state after acute coronary syndrome (55.1% with Q-wave myocardial infarction, 18.5% with non-Q myocardial infarction, 25.5% with unstable angina, men BNP level 624.5+/-32.13 mol/ml [70.3 - 4276.6]). Duration of followup was 2 years. Baseline BNP level in patients with unfavorable outcome during followup (fatal and nonfatal myocardial infarction and stroke) was 872.47+/-91.42 compared with 592.45+/-35.97 mol/ml in patients without unfavorable outcome (p=0,001). Multifactorial Cox analysis showed that carriage of T allele of polymorphic marker (--1654) of protein C gene, elevated BNP level, symptomatic atherosclerosis of peripheral arteries, history of MI, and use of thiazide diuretics were independently associated with unfavorable outcomes (p=0.026, <0.0001, <0.0001, =0.001, =0.024, respectively). Thus genetic factors and study of BNP allow to improve prediction of unfavorable outcome after exacerbation of IHD.

[Polymorphic markers Ala455Val of the THBD gene and Arg353Gln of the F7 gene and association with unfavorable outcomes of coronary atherosclerosis in patients with a history of acute ischemic heart disease].

The polymorphic markers Ala455Val of the THBD gene and Arg353Gln of the F7 gene were tested for association with the frequency of unfavorable outcomes in patients with a history of acute ischemic heart disease. The study involved 1145 patients hospitalized in cardiology clinics of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol, and Rostov-on-Don because of acute ischemic heart disease. The patients were followed up for up to 62.5 months. None of the markers displayed a significant association with the time to an endpoint. The patients were then grouped by sex. In females, the frequency of unfavorable outcomes (fatal or nonfatal myocardial infarction and fatal or nonfatal stroke) was higher in carriers of allele Val of the Ala344Val polymorphic marker of the THBD gene and carriers of genotype Arg/Arg of the Arg353Gln polymorphic marker of the F7 gene, but the difference was not statistically significant. Such an increase in frequency was not observed in males. To study the combined effect of the polymorphic markers of the THBD and F7 genes, the course of ischemic heart disease was compared for two female subgroups. One included carriers of allele Val of the Ala344Val polymorphic marker of the THBD gene and genotype Arg/Arg of the Arg353Gln polymorphic marker of the F7 gene; the other subgroup included carriers ofgenotype Ala/Ala of the Ala455Val polymorphic marker of the THBD gene and allele Gln of the Arg353Gln polymorphic marker of the F7 gene. The frequency of unfavorable outcomes in the first subgroup was higher than in the second one. The time to an endpoin was 40.5 months (95% confidence interval (CI) 33.5-47.6) in the first subgroup and 51.6 months (95% CI 45.0-58.1) in the second subgroup (chi2 = 4.15, P = 0.042). The results made it possible to assume that the F7 and THBD genes play an important role in genetic predisposition to unfavorable outcomes in patients with a history of acute ischemic heart disease.

[Gene IL6 G(-174)C and gene IL10 G(-1082)A polymorphisms are associated with unfavourable outcomes in patients with acute coronary syndrome].

We investigated the association of gene IL6 G(-174)C polymorphism and gene IL10 G(-1082)A polymorphism with coronary artery disease (CAD) in the Russian population. A total of 1145 patients with CAD diagnose on the basis of clinical studies in cardiological hospitals of Moscow, St -Petersburg, Kazan, Chelyabinsk, Perm, Stavropol and Rostov-on-Don. Supervision term was 9.10 +/- 5.03 months (the maximum term 18 months). In case of gene IL10 G(-1082)A polymorphism we determined that patients with CAD diagnose and A alleles gene IL10 had unfavorable outcome more often than patients with homozygous G alleles. Survival time from end point from carrier genotype GA and AA is 11.68 +/- 0.67 months against 12.69 +/- 0.65 months from carrier phenotype GG gene IL10 (chi2 = 4.13, p = 0.042). The group studied do not differ significantly with respect to the distributions of gene IL6 G(-174)C alleles and genotypes. However in case combined group studies of gene IL10 G(-1082)A polymorphism and IL6 G(-174)C polymorphism we determined that patients with CAD diagnose and carrier genotype GG gene IL6 and genotype GA and AA gene IL10 had unfavorable outcome more often (survival time 11.01 +/- 1.24 months) than patients with genotype CC and CG gene IL6 and genotype GG gene IL10 (survival time 13.28 +/- 0.83 months) chi2 = 10.23, p = 0.017. The obtained data allows assuming the important role of the IL6 and IL10 genes which are responsible for functioning of inflammation system, in the accelerated formation of failures at the patients who had a coronary syndrome.

[Polymorphic markers G(-455)A of gene FGB and C(-1654)T of gene PROC and genetic predisposition to unfavorable outcomes patients undergoing acute coronary syndrome].

We investigated the association of polymorphisms of genes FGB G(-455)A and PROCC(-1654)T with coronary artery disease (CAD) in the Russian population. A total of 1145 patients with CAD diagnose on the basis of clinical studies in cardiological hospitals of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol and Rostov-on-Don. Supervision term was 1.14 +/- +/- 0.33 years (the maximum term 3.2 years). The group studied do not differ significantly with respect to the distributions of G(-455)A alleles and genotypes. However in case of gene PROC C(-1654)T polymorphism we determined that patients with CAD diagnose and Talleles of PROC gene had unfavorable outcome more often than patients with homozygous C alleles. Survival time from end point from carrier phenotype TT and CTis 2.19 +/- 0.18 r. years against 2.46 +/- 0.16 from carrier phenotype CCgene PROC. The obtained data allows to assume the important role of the genes which are responsible for functioning of system of a hemostasis, in the accelerated formation of failures at the patients who had a coronary syndrome.

[Genetic predisposition to development of atrial fibrillation in patients with hypertensive disease].

We studied associations of genes of adrenoreceptor types 1, 2 and 3 (ADRB1, ADRB2, ADRB3), connexin (CX40) and voltage gated potassium channel type 2 (KCNH2) with development of atrial fibrillation (AF) in patients with hypertensive disease. We examined 102 patients with hypertensive disease which in 51 was complicated with AF. The groups were comparable by sex, age, Ketle index, presence of concomitant diseases. We determined alleles and genotypes of polymorphic markers G(-44)A and A71G of CX40 gene, Lys897Thr of KCNH2 gene, Ser49Gly of ADRB1 gene, Trp64Arg of ADRB3 gene with the help of PCR. Left atrial volume turned out to be significantly higher in patients with AF (88.7 +/- 4.13 ml and 65.4 +/- 3.96 ml, respectively, p = 0.001). No associations of genotypes of polymorphic markers Ser49Glu of ADRB1 gene, G(-44)A and A 71G of CX40 gene, Lys897Thr of KCNH2 gene, with emergence of AF in patients with arterial hypertension were revealed. For polymorphic marker Trp64Arg of ADRB3 gene frequency of Trp allele turned out to be significantly higher (OR 2.20, p = 0.0176), while frequency of Arg allele significantly lower (OR 0.43, p = 0.0176) in the group of patients with AF. In patients with AF frequency of Arg/ Arg genotype turned out to be significantly lower (OR 0.24, p = 0.0257).

[Myocardial hypertrophy in patients with hypertensive disease: the role of genetic polymorphism of beta-adrenoreactive structures].

Aim of the study was investigation of association of polymorphic markers Gly389Arg and Ser49Gly of ADRB1 gene, Gly1l6Arg and Glu27Gln of ADRB2 gene, Trp64Arg of ADRB3 gene, and 825 of GNB3 gene with structural and functional peculiarities of the left ventricular (LV) myocardium in patients with hypertensive disease. We examined 177 patients - 83 (46.9%) men and 94 (53.1%) women. Mean age was 60.6 +/- 0.76 years. In the studied group there were 19 patients (10.9%) with I degree arterial hypertension (AH), 57 patients (32.8%) with II degree AH, and 101 patients (56.3%) with III degree AH. Structural peculiarities of LV myocardium were investigated with the help of echocardiography. There turned out to be 40 patients without signs of LV hypertrophy and 137 patients with increase of LV myocardial mass index. patients with LV hypertrophy had higher frequency of genotype Arg/Arg of polymorphic maker Gly398Arg of ADRB1 gene (=0.008. OR 2.32 [CI 1.34 - 4.11]). In patients with concentric and eccentric hypertrophy significantly higher frequency of Arg/Arg genotype compared with patients with normal LV geometry and concentric LV remodeling was also noted. At conduction of multifactorial analysis independently connected with increase of LV myocardial mass turned out age of patients, level of systolic arterial pressure, presence of excessive body mass and carriage of Arg/Arg genotype of polymorphic marker Gly389Arg of ADRB1 gene.

[Associations of hemostasis factors genes with early development of ischemic heart disease and manifestation of myocardial infarction in young age].

AIM: To study polymorphisms of genes of factors of the system of hemostasis in young patients with ischemic heart disease (IHD). MATERIAL: Two groups of patients participated in the study: patients with first manifestation of IHD at the age < or = 50 years (men) or < or = 55 years (women) (n=158), and patients with first IHD manifestation at the age > or = 70 years (n=92). METHODS: We studied polymorphic markers of genes encoding clotting factors V (F5) and VII (F7), subunit IIIa of platelet integrin (ITGB3), beta-chain of fibrinogen (FGB) and tissue plasminogen activator type 1 (PLANH1). RESULTS: After separation of a subgroup of patients with MI without preceding angina we revealed significant differences in distribution of frequencies of genotypes of polymorphic marker C(-426)T of factor V gene: genotype TT was significantly more frequent in young (14.9%) than in old (2%) patients (p=0.008). Multifactorial logistic regression revealed independent association of early IHD with smoking (OR 6.112 [2.567-14.552]; p<0.001) and presence of genotype TT of C(-426)T polymorphic marker of F5 gene (OR=9.410 [1.074-82.459]; p=0.043). CONCLUSION: Thus we obtained data on the presence of independent association between IHD risk and manifestation of MI in young age with genotype TT of polymorphic marker C(-426)T of F5 gene as well as with traditional risk factors of IHD.