Aim. To evaluate the influence of genetic markers of inflammation and fibrosis on survival rate of patients with non operated aortic stenosis (AS). The search for novel prognostically adverse factors in calcinated AS patients with none surgical treatment remains actual.Material and methods. During 2,1±0,11 years, 191 patient has been followed up (28,6% males, 78,0±0,60 y. o.) with a “natural course” of AS (aortic valve area ≤2,0 cm2). All fatal outcomes (FO) were collected. Then the clinical, biochemical and echocardiographic parameters were compared, genotypes frequencies and alleles of mononucleotide polymorphisms (MNP) G(-238)A and G(-308)A gene TNF, С(-592)A gene IL-10, Arg25Pro gene TGFβ1 in groups with FO and with none. Life duration towards FO was evaluated.Results. Fatal outcomes were registered in 71 (37,2%) of patients. Death causes were: myocardial infarction in 5, stroke in 8, sudden death in 10, chronic heart failure (CHF) in 29, thromboembolism in 5, non-cardiac cause in 14. Independent factors associated with FO were: presence of CHF III-IV FC NYHA, creatinine level, aortic valve area, myocardial mass index of the left ventricle and carriage of allele Pro MNP Arg25Pro gene TGFβ1 (р<0,05). Associations of MNP G(-238)A and G(-308)A gene TNF, as MNP С(-592)A gene IL-10 with FO were not found. Mean life duration before death in Pro MNP Arg25Pro gene TGFβ1 carriers was 468,6±99,62 days versus 617,6±77,19 days in non-carriers (р<0,05).Conclusion. The carriage of allele Pro MNP Arg25Pro gene TGFβ1 can be regarded as one more predictor of fatal outcome in patients with non-operated AS. It is clear that LV myocardial fibrosis, developing in AS patients, might be a factor significantly influencing prognosis.

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.

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

С целью исследования ассоциации генов FTO, KCNJ11, SLC30A8 и CDKN2B с сахарным диабетом (СД) типа 2 изучали распределение частот аллелей и генотипов некоторых полиморфных маркеров этих генов. Сравнительный анализ распределения частот аллелей и генотипов при патологии и у здоровых людей указывает на то, что гены KCNJ11, SLC30A8 и CDKN2B (но не ген FTO) действительно ассоциированы с этим заболеванием. В исследованной нами русской популяции основную роль в развитии СД типа 2 играют гены, влияющие на уровень синтеза и секреции инсулина в -клетках поджелудочной железы.

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.

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.

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.

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.

To study the association with diabetes mellitus type 2 we performed analysis of the distribution of frequencies of alleles and genotypes two polymorphic markers of TCF7L2 gene. 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 marker rs7903146 of TCF7L2 gene showed the presence of association with T2DM in Russian population, while for the marker rs12255372 was not found statistically significant associations with type 2 diabetes. We can conclude that in Russian population TCF7L2 gene is associated with development of T2DM.

To study the distribution of alleles and genotypes of polymorphic markers of genes CYP2C9 and VKORC1 of Russian patients who live in Moscow, and in order to assess the influence of genetic factors on warfarin therapy 400 patients have been genotyped. The dosage of warfarin which is required for achievement of INR target values has been different among owners of different geno- types of polymorphic markers of genes CYP2C9 . Meanwhile the highest average dose has been required for genotype *1/*1 and the lowest – for owners of alleles *2 and *3 . For polymorphism G(- 1639)A of the gene VKORC1 the dosage of warfarin which is required for achievement of the INR target values, has been different among owners of different genotypes. The highest average dose has been required for genotype GG, and the lowest – for genotype AA. The results will allow to work out more accurate algorithm of choosing of the initial dose of warfarin depending on the genotypes of polymorphic markers of genes CYP2C9 and VKORC1.

The aim of this study was to investigate an association of polymorphic markers G(-308)A of TNF gene and Thr26Asn of LTA gene with the frequency of poor outcomes in patients with the history of acute coronary syndrome.Methods. A total of 1145 patients admitted to cardiological hospitals of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol, and Rostov-on-Don with ischemic heart disease exacerbation were examined. The maximum follow up time was 3.2 years. The identification of polymorphic marker allele was carried out by hybridization-fluorescent analysis using real-time polymerase chain reaction.Results. In case of Thr26Asn polymorphic marker of LTA gene we have not found any association with the frequency of poor outcomes in patients with the history of acute coronary syndrome. However, in case of G(-308)A polymorphic marker of TNF gene we have found the reliable association. The carriers of GA and AA genotypes has higher frequency of poor outcomes in comparison with the carriers of GG genotypes. The survival time to the endpoint for carriers of the GA and AA genotypes was 43.3 months (95% CI = 40.04 - 46.56) vs. 49.6 months (95% CI = 47.38 - 51.82) for carriers of theGG genotype (χ2 = 15.4; р < 0.001).The results of our study allow to make a conclusion that the G(-308)A polymorphic marker of TNF gene is significantly associated with hereditary predisposition to unfavourable outcome in patients with history of acute coronary syndrome.

Для изучения распределения аллелей и генотипов полиморфных маркеров генов CYP2C9 и VKORC1 у русских больных, проживающих в г. Москве, и оценки влияния генетических факторов на терапию варфарином было проведено генотипирование 400 пациентов. Дозировка варфарина, необходимая для достижения целевых значений МНО, различалась у носителей различных генотипов полиморфных маркеров гена CYP2C9 , при этом наибольшая средняя доза требовалась для носителей генотипа *1/*1 , а наименьшая – для носителей аллелей *2 и *3 . Для полиморфного маркера G(-1639)A гена VKORC1 дозировка варфарина, необходимая для достижения целевых значений МНО, различалась у носителей различных генотипов, наибольшая средняя доза требовалась носителям генотипа GG , а наименьшая – носителям генотипа AA . Полученные данные позволят разработать более точный алгоритм выбора начальной дозы варфарина в зависимости от генотипов полиморфных маркеров генов CYP2C9 и VKORC1 .

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.

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 of genotype 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 (χ2 = 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.

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.

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.

Определены частоты неблагоприятных исходов в группе пациентов, перенесших острый коронарный синдром, в зависимости от генотипов полиморфных маркеров G(–174)C гена IL6 и G(–1082)A гена IL10. Исследовали 1145 больных, госпитализированных в кардиологические стационары Москвы, Санкт-Петербурга, Казани, Челябинска, Перми, Ставрополя и Ростова-на-Дону в связи с обострением ИБС. Средний срок наблюдения – 9.10 ± 5.03 мес. (максимальный срок 18 мес.). Анализ выживаемости больных, перенесших острый коронарный синдром и являющихся носителями аллеля A, показал, что в случае маркера G(–1082)A гена IL10 чаще наблюдается неблагоприятный исход – по сравнению с носителями генотипа GG. Время дожития до конечной точки у носителей генотипов GA и AA составило 11.68 ± 0.67 мес. против 12.69 ± 0.65 мес. у носителей генотипа GG гена IL10 ( 2 = 4.13, р = 0.042). В случае маркера G(–174)C гена IL6 анализ выживаемости показал, что значимой ассоциации с риском развития неблагоприятного исхода нет. Однако при одновременном рассмотрении полиморфных маркеров обоих генов обнаружено, что в случае больных, перенесших острый коронарный синдром и являющихся носителями генотипа GG гена IL6 и генотипов GA и AA гена IL10, чаще наблюдался неблагоприятный исход (время дожития 11.01 ± 1.24 мес.) – по сравнению с носителями генотипов CC и CG гена IL6 и генотипа GG гена IL10 (время дожития 13.28 ± 0.83 мес., 2 = 10.23, р = 0.017). Эти данные позволяют предположить, что гены IL6 и IL10, продукты которых контролируют воспалительные процессы, играют важную роль, увеличивая вероятность неблагоприятных исходов у больных, перенесших острый коронарный синдром.