Aim. To analyze the association between the polymorphic markers in CTLA4, TNF, IL10 and IL16 genes and the risk of manifestation of endocrine ophthalmopathy (EO) in patients with Graves’ disease (GD). Materials and methods. Case-control study included 248 patients with GD. Using polymerase chain reaction we studied the distribution of alleles and genotypes of polymorphic markers such as A60G (rs3087243) in CTLA4 gene, G(-308)A (rs1800629) in TNF gene, G(-1082)A (rs1800896) in IL10 gene, T3249C (rs4778641) in IL16 gene among 141 patients with Graves’ disease and EO and 107 patients with GD without EO. Results and discussion. The frequencies of A alleles and the AA genotypes were significantly increased and the frequencies of G alleles and the GG genotype polymorphic markers rs3087243 of CTLA4 gene and rs1800896 of IL10 gene, as well as the GG genotype polymorphic marker rs1800629 of TNF gene were reduced in patients with GD and EO. The polymorphism in CTLA4 gene was also associated with the activity and the severity of EO. The comparative analysis of the allele and genotype frequency distribution of polymorphic markers of IL16 gene did not show the significant difference. Conclusion. The risk of manifestation and the development of EO in patients with Graves’ disease can be caused by not only environmental, but also genetic risk factors.

Patients with diabetes mellitus (DM) represent a risk group for developing chronic kidney disease (CKD), the terminal stages of which require renal replacement therapy. The study of genetic predisposition to CKD is of special significance from the perspective of the prediction and identification of risk groups at the preclinical stage. The present study is a review of the world literature on the genetics of CKD in diabetes and also includes data of our own studies.

Background The association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes. Methods The study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-β were used to measure insulin resistance and β-cell secretory function, respectively. Results The analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired β-cell function. Conclusion In the Russian population, genes, which affect insulin synthesis and secretion in the β-cells of the pancreas, play a central role in the development of T2DM.

AIM:To study the association of the polymorphic markers (PMs) G(-238)A of the TNF gene, G(-174)C of the IL-6 gene, and G(-1082)A of the IL-10 gene with the clinical characteristics of chronic glomerulonephritis (CGN) and a response to immunosuppressive therapy (IST).SUBJECTS AND METHODS:Clinical syndromes at the time of diagnosis, the morphological types of nephritis, and a response to IST were analyzed in relation to the carriage of the examined PMs of the TNF, IL-6, and IL-10 genes in 102 patients with CGN.RESULTS:No association was found between the PM G(-238)A of the TNF gene and the clinical features of CGN. The carriers of the C allele of the PM G(-174) C of the IL-6 gene versus the homozygous individuals were observed to have more frequently kidney dysfunction at the time of diagnosis (р=0.014). Hypertension was more common in the carriers of the AA genotype of the PM G(-1082)A of the IL-10 gene (p=0.023); moreover, they tended to have a more frequent concurrence of nephrotic syndrome and hypertension (p=0.082). Analysis of the distribution of the morphological types of CGN disclosed that the proliferative variants were more common in the patients with the GG genotype (the TNF gene) as compared to the A allele carriers (p=0.067); and the nonproliferative forms were in the individuals homozygous for GG (the IL-6 gene) as compared to the C allele carriers (p=0.067). Examination of an IST response showed that a complete response at 12 months of treatment occurred more frequently in the carriers of the C allele of the IL-6 gene (p=0.045) and in those of the GG genotypes of the IL-10 gene (p=0.030).CONCLUSION:There was an association of the PMs G(-174)C of the IL-6 gene and G(-1082)A of the IL-10 gene with the clinical features of CGN and a response to IST.

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 polymorphic ADPRT1 gene Val762Ala marker, encoding poly(ADP-ribose)polymerase-l, with the development, course and progress of chronic glomerulonephritis was revealed during investigation. The risk of the chronic glomerulonephritis development is higher in patients-carriers of Val-allele and Val/Val-genotype and lower in those with Ala-allele and Ala/Ala-genotype.

The article focuses on the application of the Bayesian networks (BN) technique to problems of personalized medicine. The simple (intuitive) algorithm of BN optimization with respect to the number of nodes using naive network topology is developed. This algorithm allows to increase the BN prediction quality and to identify the most important variables of the network. The parallel program implementing the algorithm has demonstrated good scalability with an increase in the computational cores number, and it can be applied to the large patients database containing thousands of variables. This program is applied for the prediction for the unfavorable outcome of coronary artery disease (CAD) for patients who survived the acute coronary syndrome (ACS). As a result, the quality of the predictions of the investigated networks was significantly improved and the most important risk factors were detected. The significance of the tumor necrosis factor-alpha gene polymorphism for the prediction of the unfavorable outcome of CAD for patients survived after ACS was revealed for the first time.

The study of hereditary predisposition to multifactorial diseases is essential for diagnosis and selection of the optimal treatment. The study of polymorphisms of candidate genes whose products are involved in the pathogenesis of multifactorial diseases is of great clinical importance. Aim. The aim of this study was to investigate the association of rs2241766 and rs1501299 polymorphisms in the ADIPOQ gene, rs2275737 and rs2275738 polymorphisms in the ADIPOR1 gene and rs11061971 and rs16928751 polymorphisms in the ADIPOR2 gene with the development of type 2 diabetes mellitus (T2DM) in the Russian population. Materials and methods. The study included a group of 500 patients with T2DM diagnosed based on standard diagnostic criteria (T2DM+). The control group (T2DM-) was a random sample of 500 patients with no evidence of the disease and was matched to the T2DM+ group for gender, age and body mass index. The determination of alleles and genotypes was performed using real-time polymerase chain reaction with TaqMan probes. The X2 test and contingency tables were used to compare the distribution of allele and genotype frequencies. A p-value of

To test FTO, KCNJ11, SLC30A8, and CDKN2B for association with type 2 diabetes mellitus (DM), the allele and genotype frequency distributions were established for several polymorphisms of the genes. A comparison of allele and genotype frequencies between DM patients and healthy subjects implicated CKNJ11, SLC30A8, and CDKN2B, but not FTO, in the disease. The genes that affect insulin production and secretion in pancreatic β cells proved to play a main role in type 2 DM in the Russian population.

It can be suggested that development of atrial fibrillation (AF) in patients with chronic obstructive pulmonary disease (COPD) is directly related to the system of inflammation. Genetic polymorphism of factors of this system can be one of components of mechanism of AF in COPD. Aim: to elucidate polymorphic markers of genes of factors of the system of inflammation associated with AF in patients with COPD. Material and methods. We examined 208 patients with COPD (52 with and 156 without AF). Examination included spirometry, echocardiography, and study of frequencies of polymorphic markers G(-238)A, G(-308)A of tumor necrosis factor (TNF) gene, C(-819)T of interleukin (IL) 10 gene, G(-174)C of IL-6 gene, rs2228145(A/C) of IL-6R gene, and rs2069762(A/C) of IL-2 gene. Results. Factors associated with AF were left atrial volume (odds ratio [OR] 1.021, 95% confidence interval [CI] 1.004-1.043, p= 0,027), right atrial volume (OR 1.02, 95% CI 1.001-1.040, p=0.021), and carriage of C allele of polymorphic marker G(-174)C of IL-6 gene (OR 6.02, 95% CI 1.87-19.38, p= 0.003). Conclusion. C allele of polymorphic marker G(-174)C of IL-6 gene can be considered to be independently associated with development of AF in patients with COPD.

Aim. To reveal the association of hereditary specifics of inflammatory factors with the adverse risk in atrial fibrillation (AF).Material and methods. Totally 258 patients studied (68,5±0,67 y. o.) with nonvalvular AF, recording the events as ischemic stroke, myocardial infarction, venous and arterial thromboembolism. Mean follow-up was 455±11,71 days.Results. Factors that are independently associated with ischemic stroke development in patients not receiving anticoagulants (n=101), were the allele C of polymorphic marker rs2228145(А/С) of gene IL-6 receptor (OR 13,25 CI 1,57112,18, р=0,018), age ?75 y. o. (OR 1,1, CI 1,008-1,2, р=0,032) and EF LV (OR 0,97 CI 0,94-0,99 р=0,027), with a “thrombotic endpoint” development — DM (OR 4,3 CI 1,46-12,45 р=0,008), EF LV (OR 0,96 CI 0,94-0,98, р<0,0001) and carriage of allele C of polymorphic marker rs2228145(А/С) of receptor to IL-6 gene (OR 4,03 CI 1,0715,26, р=0,04). There was no association with adverse outcomes in genes IL-6 polymorphisms as (G(-174)C and G(-572)C), ИЛ-10 (C(-819)T), ФНО (G(-238)A, G(-308)A and ФНО? rs180630). In those receiving adequate anticoagulant therapy (n=157) there was no significant association of IL-6 receptor gene polymorphism with adverse outcomes.Conclusion. Therefore, the carriage of allele C of polymorphic marker rs2228145(А/С) of the IL-6 receptor gene might be an independent risk marker for adverse outcome in non-valvular AF, potentially, being a selection tool for those patients not having enough high risk according to common scores.

Diabetic neuropathy (DN) represents the main cause of morbidity and mortality among diabetic patients. Clinical data support the conclusion that the severity of DN is related to the frequency and duration of hyperglycemic periods. The presented experimental and clinical evidences propose that changes in cellular function resulting in oxidative stress act as a leading factor in the development and progression of DN. Hyperglycemia- and dyslipidemia-driven oxidative stress is a major contributor, enhanced by advanced glycation end product (AGE) formation and polyol pathway activation. There are several polymorphous pathways that lead to oxidative stress in the peripheral nervous system in chronic hyperglycemia. This article demonstrates the origin of oxidative stress derived from glycation reactions and genetic variations within the antioxidant genes which could be implicated in the pathogenesis of DN. In the diabetic state, unchecked superoxide accumulation and resultant increases in polyol pathway activity, AGEs accumulation, protein kinase C activity, and hexosamine flux trigger a feed-forward system of progressive cellular dysfunction. In nerve, this confluence of metabolic and vascular disturbances leads to impaired neural function and loss of neurotrophic support, and over the long term, can mediate apoptosis of neurons and Schwann cells, the glial cells of the peripheral nervous system. In this article, we consider AGE-mediated reactive oxygen species (ROS) generation as a pathogenesis factor in the development of DN. It is likely that oxidative modification of proteins and other biomolecules might be the consequence of local generation of superoxide on the interaction of the residues of l-lysine (and probably other amino acids) with α-ketoaldehydes. This phenomenon of non-enzymatic superoxide generation might be an element of autocatalytic intensification of pathophysiological action of carbonyl stress. Glyoxal and methylglyoxal formed during metabolic pathway are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. Genetic variations within the antioxidant genes therefore could be implicated in the pathogenesis of DN. In this work, the supporting data about the association between the −262T > C polymorphism of the catalase (CAT) gene and DN were shown. The −262TT genotype of the CAT gene was significantly associated with higher erythrocyte catalase activity in blood of DN patients compared to the −262CC genotype (17.8 ± 2.7 × 104 IU/g Hb vs. 13.5 ± 3.2 × 104 IU/g Hb, P = 0.0022). The role of these factors in the development of diabetic complications and the prospective prevention of DN by supplementation in formulations of transglycating imidazole-containing peptide-based antioxidants (non-hydrolyzed carnosine, carcinine, n-acetylcarcinine) scavenging ROS in the glycation reaction, modifying the activity of enzymic and non-enzymic antioxidant defenses that participate in metabolic processes with ability of controlling at transcriptional levels the differential expression of several genes encoding antioxidant enzymes inherent to DN in Type I Diabetic patients, now deserve investigation.

AIM:to elucidate association between polymorphic markers of interleukin-6 (Il-6) and tumor necrosis factor (TNF) genes and unfavorable outcomes in patients with chronic heart failure (CHF).MATERIAL AND METHODS:We determined levels of TNF and Il-6 and genotypes of polymorphic markers G(-238)A of TNF gene (rs361525) and G(--174)C of IL-6 gene (rs1800795) in 151 patients (mean age 64.5 years) hospitalized because of decompensation of systolic CHF (left ventricular ejection fraction ≤ 40%) after stabilization of their state. Unfavorable outcomes were registered during follow-up for 2 years.RESULTS:Mean levels of NT-proBNP, Il-6, and TNF were 2481.1 ± 199.86 fmol/ml, 21.8 7.46 rg/ml, and 10.07 ± 0.65 rg/ml, respectively. 138 (94.4%), 13 (8.6%) and 0 patients were carriers of genotypes GG, AG, and AA of polymorphic marker G(-238)A of TNF gene, respectively; 54 (35.8%), 69 (45.7%), and 28 (18.5%) patients carried genotypes GG, GC, and CC of polymorphic marker G(-174)C gene IL-6, respectively. There was no association between Il-6, TNF levels and carriage of either of genotypes as well as unfavorable clinical course of CHF. Mean survival time before repetitive episode of CHF decompensation (including lethal one) was significantly shorter among carriers of A allele compared with carriers of G allele of polymorphic marker G(-238)A of TNF gene (243 ± 97.7 and 947 ± 78 days, respectively, p = 0.018). Mean time before all cause death was also shorter in carriers of A compared with carriers of G allele (289 ± 122.9 and 1039 ± 73.3 days, respectively, p = 0.03). The studied polymorphism of IL-6 gene had no prognostic value.CONCLUSION:We obtained data on association between carriage of A allele of polymorphic marker G(-238)A of TNF gene and unfavorable prognosis in patients with CHF and inpraired left ventricular systolic function.

Целью исследования было проанализировать взаимосвязь эффективности бетаксолола при лечении больных ГБ с полиморфизмом генов, кодирующих бета-адренорецепторы и ферменты системы цитохромов Р450. Определение аллелей и генотипов полиморфных маркеров Ser49Gly в гене ADRB1, T(-47)C гена ADRB2, Trp64Arg гена ADRB3, Ile462Val гена CYP1A1, A(-163)C гена CYP1A2 и Pro34Ser гена CYP2D6 проводилось с помощью полимеразной цепной реакции. Обследован 81 больной ГБ (35 мужчин и 46 женщин), средний возраст составил 52,2±1.22 года, 39 имели артериальную гипертонию 1 степени тяжести и 42– 2 степени тяжести, средняя длительность заболевания на момент включения в исследование 6,8±1.21 лет. Терапия бетаксололом в дозе 10 мг/сут проводилась в течение 28 дней. Исходно и на 28-й день терапии проводилось измерение артериального давления, суточное мониторирование АД и выполнялся нагрузочный тест. При изучении эффективности бетаксолола у больных МА обследовано 55 пациентов, из них 31 мужчина и 24 женщины, средний возраст – 67,9 ±1,34 лет. Бетаксолол назначался в дозе 10 мг в сутки в течение не менее 5 дней. Выявлено, что применение бетаксолола у больных мерцательной аритмией является эффективным в отношении контроля ЧСС, однако имеется выраженная вариабельность эффекта. При лечении ГБ антигипертензивная эффективность бетаксолола и его отрицательный хронотропный эффект также отличается значимой вариабельностью. Для этих двух заболеваний показана ассоциация эффективности бетаксолола с носительством генотипа СС полиморфного маркера А(-163)С гена CYP1A2. Высокая эффективность бетаксолола у этих больных может быть связана со снижением скорости метаболизма препарата. Выявленные ассоциации показаны на сравнительно небольшой группе больных, что требует дальнейших исследований. Ключевые слова: мерцательная аритмия, гипертоническая болезнь. The purpose of the present study was to analyze correlation between Betaxolol effectiveness and polymorphisms of genes coding β-adrenoreceptors and enzymes in the cytochrome system Р450 in patients with hypertensive disease. Alleles and genotypes of polymorphous markers Ser49Gly in gene ADRB1, T(-47)C of gene ADRB2, Trp64Arg of gene ADRB3, Ile462Val of gene CYP1A1, A(-163)C of gene CYP1A2 and Pro34Ser of gene CYP2D6 were determined using the polymerase chain reaction. 81 patient (35 men and 46 women) with hypertensive disease, aged 52.2±1.22, were examined. 39 of them had arterial hypertension of stage I; 42 –stage II; average course of the disease at the moment of recruitment into the study was 6.8±1.21 years. Betaxolol was prescribed at the dosage 10 mg/day during 28 days. Arterial blood pressure (AP) measurements, day-round AP monitoring and load-tests were done initially and on the 28th day of treatment. To study Betaxolol effectiveness in patients with ciliary arrhythmia 55 patients ( 31 men and 24 women with average age 67.9 ±1.34) were recruited into the study. Betaxolol was prescribed for them at the dosage 10mg per day for not less than 5 days. It has been found out that Betaxolol prescribed for patients with ciliary arrhythmia was effective for controlling heart rate though this effectiveness was variable. In treating hypertensive disease with Betaxolol one can see that its antihypertensive effect and its negative chronotropic effect were also variable. Correlation between Betaxolol effectiveness and genotype CC of polymorphous marker А(-163)С of gene CYP1A2 for these two diseases has been shown as well. High effectiveness of Betaxolol in these patients may be explained by the decreased rate of preparation metabolism. These above mentioned correlations were revealed at a relatively small group of patients; thus, further researches should be made to confirm conclusions. Key words: ciliary arrhythmia, hypertensive disease.