The most common cause of transient loss of consciousness is vasovagal syncope (VVS), which occurs owing to hypoperfusion of the brain due to the interruption of vegetative blood circulation control leading to arterial hypotension. It is known that there is a genetic predisposition to VVS, but the data on the role of individual genes are quite inconsistent. Using APSampler software, which is based on a Markov chain Monte Carlo technique and Bayesian nonparametric statistics, we identified biallelic combinations associated with VVS and investigated the nature of interaction between their components. We used the previously obtained results of genomic typing of single nucleotide polymorphisms (SNPs) of five genes the products of which are involved in neurohumoral regulation and four SNPs within locus 2q32.1, supplemented with data for new individuals included in the study. The total sample included 175 patients with a confirmed diagnosis of VVS and 200 control individuals without a history of syncope. Eleven pairwise combinations of SNPs of different genes were found to be associated with VVS. Five of these combinations were epistatic, four of which included SNPs at the 2q32.1 locus located within or near noncoding RNA genes. It is suggested that genes of noncoding RNAs localized on chromosome 2 may directly or indirectly (through cascades of interactions) participate in the regulation of the activity of genes forming epistatic combinations with them.

—The vasovagal syncope (VVS) is the most common form of syncope. The mechanisms of VVS development are not entirely clear. It is known that there is a genetic predisposition to this disease, but the data on the roles of individual genes are quite contradictory. Recently, a genome-wide association study identified a locus at chromosome 2q32.1 associated with a united group of diseases, that is, syncope and collapse; among the single nucleotide polymorphisms (SNPs) of this locus, the most significant association was observed for rs12465214. In a homogeneous sample of patients diagnosed with VVS, we analyzed the association of rs12465214, rs12621296, rs17582219 and rs1344706 located on chromosome 2q32.1 with this form of syncope. In the enrolled set, only rs12621296 was associated with VVS by itself, whereas associations of other SNPs were observed only in biallelic combinations. An epistatic interaction between the components of the combination rs12621296*A + rs17582219*A was revealed. The possible involvement of individual genes on the 2q32.1 locus in the genetic architecture of the VVS is discussed.

MicroRNA (miRNA) miR-375 acts as a multifunctional regulator of the activity of many physiological and pathological cellular processes by interacting with a large number of target genes. MiR-375 is involved in the regulation of the differentiation and functioning of cells of the nervous and immune systems, bone and adipose tissue, and even the life cycle of a number of viruses. Changes in miR-375 expression have been found in carcinogenesis, inflammation, and autoimmune and cardiovascular diseases. Every year, new studies appear that expand our understanding of the range of processes regulated by this miRNA. According to the latest data, miR-375 can be used as a biomarker and therapeutic target in some diseases. This review discusses the role of miR-375 in the functioning of the cardiovascular system in health and disease.

В последние годы стало понятно, что микроРНК играют большую роль в развитии и функционировании сердечно-сосудистой системы в норме и при патологии. Взаимодействуя с большим числом генов-мишеней, они работают как многофункциональные регуляторы различных внутриклеточных сигнальных путей. Одна из таких микроРНК — miR-375, которая вовлечена в развитие многих сердечно-сосудистых заболеваний. Конкретные механизмы и следствия ее регуляторного влияния до сих пор не выяснены окончательно. ЦЕЛЬ ИССЛЕДОВАНИЯ На клеточной модели эндотелиальных клеток оценить влияние повышения уровня miR-375 на экспрессию генов, связанных с сердечно-сосудистыми заболеваниями. МАТЕРИАЛ И МЕТОДЫ Для оценки влияния повышенного уровня miR-375 на экспрессию генов проведена трансфекция клеток HUVEC мимиком miR-375 и контрольным олигонуклеотидом, не комплементарным известным РНК человека, и последующее транскрипционное профилирование методом высокопроизводительного секвенирования РНК. Пролиферативную активность и уровень апоптоза в трансфицированных клетках оценивали с помощью МТТ-теста и проточной цитофлуориметрии после двойного окрашивания аннексином V, меченным FITC, и йодидом пропидия. РЕЗУЛЬТАТЫ Анализ полнотранскриптомных профилей показал, что при повышении уровня miR-375 в клетках HUVEC динамически изменялась экспрессия ряда генов, в числе которых ген интерлейкина 8 CXCL8 и микроРНК miR-596. Общими мишенями для miR-375 и miR-596 оказались гены MCL1, WWC2, CNBP и SOX4. ЗАКЛЮЧЕНИЕ Повышение уровня miR-375 в клетках HUVEC приводит к динамическому изменению транскриптома. Наиболее перспективными для дальнейшего изучения регуляторной роли miR-375 в эндотелиальных клетках нам представляются гены CXCL8 и WWC2, продукты которых участвуют в развитии сердечно-сосудистой системы и в патогенезе сердечно-сосудистых заболеваний, а также ген микроРНК miR-596.

Rationale. Cardiovascular diseases remain the leading cause of human death in the world. Studying the role of regulatory non-coding RNAs, which include short single-stranded miRNA molecules, allows a more detailed understanding of the pathological processes underlying the progression of atherosclerosis . Objective — to compare the levels of circulating miRNAs in patients with coronary heart disease, confirmed by multislice computed tomography-coronarography (MSCT-CA), with risks of cardiovascular complications and clinical and demographic characteristics. To compare the profiles of circulating miRNAs in groups of patients with stable and unstable atherosclerotic plaques. Methods. MicroRNA levels in the plasma of peripheral blood of patients with coronary heart disease were determined using the miScript miRNA PCR Array MIHS-105Z kit (Qiagen). The significance of differences in miRNA levels between the compared groups was determined using the Mann–Whitney U-test. The correlations of the levels of circulating miRNAs with clinical and demographic parameters were evaluated using the Spearman correlation coefficient. Risk assessment of cardiovascular complications in these patients was carried out using validated scales (ACC/AHA, Framinghm, SCORE, MESA). Atherosclerotic plaque stability was evaluated using MSCT-CA. Results. The study showed a significant (p < 0.05) decrease in miR-16, miR-211, miR-195 miRNA levels in the plasma of patients with coronary heart disease, which correlated with an increase in cardiac vascular risk (CVR) according to ACC/AHA, Framingham and MESA. When comparing groups of patients with stable and unstable atherosclerotic plaques, the latter revealed an increase in the level of let-7b-5p circulating microRNA (p < 0.05). Conclusion. Significant associations of the three studied microRNAs with the estimated risk of CVR were identified. It is important to find circulating let-7b-5p in a group of patients with unstable atherosclerotic plaques. Correlations were established between the levels of circulating microRNAs and clinical and demographic characteristics of patients. The study shows the involvement of some microRNAs in the regulation of atherosclerosis.

Atrial fibrillation (AF) is one of the most common arrhythmia that occurs in patients with cardiovascular diseases. Congenital forms of AF are quite rare. Many studies have shown that genetic, epigenetic and transcription factors may play an important role in the development and the progression of AF. In our review, studies have been conducted on the identification of mutations in ionic and non-ionic channels, possibly associated with AF. These mutations were found only in isolated groups of patients with AF, and in general, monogenic forms of AF are a rare subtype of the disease. Genomic association studies have helped to identify potential links between single nucleotide polymorphisms and AF. The risk of AF in the general population is likely to be determined by the interaction between environmental factors and many alleles. In recent years, the emergence of a genome-wide associative studies has significantly expanded the understanding of the genetic basis for the inheritance of AF and has led to the emergence of new evidence of the important role of genetic factors in the development of AF, in the risk stratification of AF and the recurrence of AF. Epigenetic factors are also important in AF. Epigenetic therapy aimed at treating a disease through exposure to epigenome is currently under development. A newly emerged area of ablatogenomics includes the use of genetic profiles that allow assessing the likelihood of recurrence of AF after catheter ablation. The results of genetic studies in AF show that, in addition to their role in the appearance of congenital heart pathologies, transcription factors play an important role in the pathogenesis of AF.

Coronary artery disease is the most clinically significant manifestation of atherosclerosis and the main cause of morbidity and mortality around the world. Atherogenesis is a complex process, involving various types of cells and regulatory molecules. MicroRNA molecules were discovered at the end of the 20th century, and nowadays are the important regulators of several pathophysiological processes of atherogenesis. The review examines data on the participation of various microRNAs in the development of atherosclerosis and its main clinical manifestations and discusses the possibility of using microRNAs as diagnostic markers for these diseases.

The heritable component of susceptibility to myocardial infraction (MI) remains unexplained, possibly due to the minor effects of genes, which are not obviously associated with the disease. These genes may be integrated in miRNA regulated networks associated with myocardial infarction. A systematic review of the literature led us to selecting rs2910164 (MIR146A), rs11614913 (MIR196A2), and rs3746444 (MIR499А) variants to study the association with the MI phenotype. In ethnic Russians, variant rs11614913*C (MIR196A2) was found to be associated with the risk of myocardial infraction (p = 0.023, OR = 1.74) for the first time; this association was validated in an independent cohort. The gene-gene interaction network for experimentally validated miR-196a2 target genes was built and analyzed. One of its four topological clusters contained the majority of miR-196a2 target genes associated with atherosclerosis, coronary artery disease or myocardial infarction and was enriched with the genes regulating the TGFβ and class I MHC signaling pathways, platelet activation/aggregation, and the cell cycle control. This analysis points towards the role of miR-196a2 in the pathological coronary phenotypes and opens up an avenue for further investigations.

The heritable component of susceptibility to myocardial infraction (MI) remains unexplained, possibly due to the minor effects of genes, which are not obviously associated with the disease. These genes may be integrated in miRNA regulated networks associated with myocardial infarction. A systematic review of the literature led us to selecting rs2910164 (MIR146A), rs11614913 (MIR196A2), and rs3746444 (MIR499А) variants to study the association with the MI phenotype. In ethnic Russians, variant rs11614913*C (MIR196A2) was found to be associated with the risk of myocardial infraction (p = 0.023, OR = 1.74) for the first time; this association was validated in an independent cohort. The gene-gene interaction network for experimentally validated miR-196a2 target genes was built and analyzed. One of its four topological clusters contained the majority of miR-196a2 target genes associated with atherosclerosis, coronary artery disease or myocardial infarction and was enriched with the genes regulating the TGFβ and class I MHC signaling pathways, platelet activation/aggregation, and the cell cycle control. This analysis points towards the role of miR-196a2 in the pathological coronary phenotypes and opens up an avenue for further investigations.

Regression analysis has been used to model the combined influence of adverse factors, namely, specific variants of the CRP (rs1130864), IFNG (rs2430561), TGFB1 (rs1982073), FGB (rs1800788), and PTGS1 (rs3842787) genes; age; and smoking on the risk of myocardial infarction in men, as well as the possible interactions between these factors. The individual effects of each considered genetic factor were comparable in strength to the influence of smoking on the risk of myocardial infarction, and the presence of a combination of two or more genetic variants in nonsmokers resulted in a higher risk of myocardial infarction than in noncarrier smokers. A significant interaction between the presence of the FGB allele rs1800788*T and age was discovered; the protective effect of this allele decreased with age and gradually transformed into a predisposing effect. The study demonstrated that the association of FGB rs1800788*T with the risk of myocardial infarction should be considered only in the context of interaction with age.

In search of genetic markers of myocardial infarction (MI) risk, which have prognostic significance for Russians, we performed a replication study of MI association with genetic variants of PCSK9 (rs562556), APOE (epsilon polymorphism, rs7412 and rs429358), LPL (rs320), MTHFR (rs1801133), eNOS (rs2070744), and the 9p21 region (rs1333049) in 405 patients with MI and 198 controls. Significant MI association was observed with variants of the lipid metabolism genes (PCSK9, APOE and LPL), and of eNOS. The SNPs in the MTHFR gene and the 9p21 region were not significantly associated with MI one by one but were included in several different MI-associated allelic combinations identified by multilocus analysis. Since we have not revealed nonlinear epistatic interactions between the components of the identified combinations, we postulate that the cumulative effect of genes that form a combination arises from the summation of their small independent contributions. The prognostic significance of the additive composite model built from the PCSK9, APOE, LPL, and eNOS genes as genetic markers was assessed using ROC analysis. After we included these markers in the previously published composite model of individual genetic risk of MI, the prognostic efficacy in our sample reached AUC = 0.676. However, the results obtained in this study certainly need to be replicated in an independent sample of Russians.

Carriage frequencies of alleles and genotypes of polymorphic loci of inflammation genes (49A>G CTLA4, 41G>A and 87C>T PDE4D, −590C>T IL4, −308A>G TNF, 252G>A LTA, 874A>T IFNG, −509С>Т, 869T>C and 915G>C TGFB1) were determined in a sample of 200 patients diagnosed with ischemic stroke and in the control group similar in gender and age (146 individuals), all ethnic Russians. The positive association of the allele PDE4D*87C (р = 0.028) and genotype TGFB1*−509Т/Т (р = 0.02) carriage with ischemic stroke was shown. The association of the disease with the carriage of the allele PDE4D*41А (р = 0.009) in individuals under the age of 60 and with carriage of the allele IFNG*874Т (р = 0.02) in individuals older than 60 was observed among the subgroups of patients stratified by age when they suffered the stroke compared to a control group of the same age. In subgroups stratified by gender, carriage of the genotype TGFB1*915G/G (р = 0.0015) was identified as a risk factor in male patients, while no significant differences between female patients and healthy women were observed. Multilocus analysis was undertaken to search for the association of several combinations of studied gene variants with ischemic stroke. The polymorphic locus–174G>C of the IL6 gene, for which an association with the disease was previously demonstrated, was also included in this analysis. The disease-predisposing biallelic combinations include the IL6*−174G, PDE4D*87C, TGFB1*−509Т and TGFB1*915G alleles. In the subgroups stratified by gender, the allelic combinations mainly include the similar risk alleles as in the total group, while between the subgroups stratified by age (patients who suffered the first stroke at the age of 18 and no older than 60 years and older than 60 years), greater differences were observed. However, a new risk allele, LTA*252G, was identified in combination with PDE4D*41А in women. These findings demonstrate the important role of inflammation in ischemic stroke. The identified single and combined markers may be used further to determine an individual risk for ischemic stroke.

OBJECTIVE:to elaborate a complex model for myocardial infarction (MI) risk assessment considering the combined effect of genetic predisposition, age and smoking. MATERIALS AND METHODS:The study included two independent samples of ethnic Russians: 325 patients with MI and 185 individuals without history of cardiovascular diseases (controls) from the Moscow region, and 220 patients and 197 controls from the Republic of Bashkortostan. Genotyping of polymorphic loci of genes CRP (rs1130864), IFNG (rs2430561), TGFB1 (rs1982073), FGB (rs1800788) and PTGS1 (rs3842787) was performed. To construct the predictive models, we used logistic regression with stepwise inclusion of variables. The predictive value was evaluated by the area under the curve (AUC) in a ROC-analysis. The factor was considered as a marker at pAUC <0.05 calculated by the method of DeLong. The marker was considered effective at AUC >0.60. RESULTS:Three separate genetic variants FGB rs1800788*T, TGFB1 rs1982073*TT, CRP rs1130864*TT, and biallelic combination IFNG rs2430561*A + PTGS1 rs3842787*T whose association with MI we described earlier, were used to construct the composite genetic marker (AUC=0.66 in the training and test samples) by the logistic regression method. Adding to the obtained composite genetic marker such parameters as age and smoking allowed to create a complex MI risk marker, which was characterized by the predictive value stability (AUC=0.77 in the training sample and 0.82 in the test sample). CONCLUSION:The obtained complex model for MI risk assessment was reproduced in two independent samples of Russian ethnicity individuals from different regions of Russia with different gender identities, and allowed to have a reasonable chance (about 80%) of distinguishing patients and healthy individuals.

В современном мире острые нарушения мозгового кровообращения (инсульты) относятся к важнейшим медико-социальным проблемам, что обусловлено их высокой долей в структуре заболеваемости, инвалидизации и смертности населения. Основную долю инсультов составляет ишемический инсульт (ИИ). ИИ представляет собой комплексное (мультифакториальное) полигенное заболевание, т.е. развивается в результате взаимодействий между традиционными факторами риска и генетической компонентой, которая формируется в результате совместного вклада множества независимо действующих или взаимодействующих полиморфных генов. В настоящее время для поиска генетической предрасположенности к ИИ используется два основных подхода, основанные на анализе ассоциации между полиморфными участками генома и заболеванием: метод “ген-кандидат” и полногеномный поиск ассоциаций (genome-wide association studies), – с последующим мета-анализом полученных результатов. В обзоре рассмотрены данные литературы по генетической предрасположенности к ИИ, которые могут стать отправной точкой для исследования молекулярных механизмов, определяющих патофизиологию ИИ. Несмотря на достигнутые успехи, до полного решения проблемы идентификации генетических факторов риска, которые можно было бы использовать как прогностические маркеры индивидуальной предрасположенности к ИИ, еще очень далеко, в основном вследствие плохой воспроизводимости результатов. Путь к решению этой проблемы лежит через исследования этнически гомогенных популяций и клинически различающихся форм ИИ.

Cerebrovascular accidents (strokes) are a challenge to modern health care throughout the world because they contribute greatly to morbidity, disability, and mortality rates. Ischemic stroke constitutes the majority of cases of cerebrovascular accidents. It is a complex multifactorial polygenic disease, i.e., it develops under the influence of conventional risk factors and the genetic component. The latter is formed by the joint contribution of many independent or interacting polymorphic genes. Current studies of the genetic susceptibility to ischemic stroke use two approaches based on the analysis of the association between polymorphic sites of the genome and the disease, including the candidate-gene approach and genome-wide association studies, followed by a meta-analysis of the results. This review considers the published data on genetic susceptibility to ischemic stroke, which may be a starting point for the investigation of molecular mechanisms that determine the pathophysiology of ischemic stroke. Although some progress has been made in this field, the problem of identifying genetic risk factors that could be used as markers for predicting individual susceptibility to ischemic stroke is still far from a complete solution. The main obstacle to this is the low replication of the results. It can be overcome by investigating ethnically uniform populations and clinically distinct IS forms.

Conditions of the formation of soluble chymotrypsin complexes with selenium nanoparticles are studied. It is established that the aggregative stability of the nanocomplexes is determined by their conditions of preparation, depending also on the medium pH and ratio of selenium: chymotrypsin concentration. It is shown that chymotrypsin has a “protective” effect due to its hydrophobic adsorption on the surface of selenium nanoparticles and hence the hydrophilization of their surfaces due to ionized groups of the protein.

Проведен анализ частот встречаемости аллелей и генотипов полиморфных участков (SNP) -509CgT (rs1800469), 869TgC (rs1982073), 915GgC (rs1800471) гена трансформирующего фактора роста бета 1 (TGFB1), влияющих на уровень продукции цитокина TGF-βΙ, у больных инфарктом миокарда (ИМ) (406 человек) и в контрольной группе (198 человек), все русские по этнической принадлежности. Наблюдали значимую позитивную ассоциацию частот носительства аллеля TGFB1*-509T (p = 0.046, ОШ = 1.45, 95% ДИ: 1.02-2.06) и генотипов TGFB1*869T/T (p = 0.0024, ОШ = 1.75, 95% ДИ: 1.22-2.51) и TGFB1*915G/G (p = 0.048, ОШ = 1.76, 95% ДИ: 1.05-2.97) с ИМ. Анализ неравновесия по сцеплению между этими SNP показал, что выявленные ассоциации можно рассматривать как не зависящие друг от друга. Комплексный анализ ассоциации ИМ с носительством сочетаний аллелей/генотипов указанных SNP свидетельствует о кумулятивных эффектах этих SNP. При анализе предрасположенности к раннему ИМ (l 50 лет) обнаружена позитивная ассоциация аллеля TGFB1*-509T (p = 0.002, ОШ = 2.24, 95% ДИ: 1.35-3.71) и генотипа TGFB1*869T/T (p = 0.008, ОШ = 1.93, 95% ДИ: 1.18-3.15), а также аддитивность их вкладов. Анализ предрасположенности к повторным ИМ выявил ассоциацию генотипа TGFB1*-509T/T (p = 0.0078, ОШ = 2.60, 95% ДИ: 1.28-5.28). Полученные результаты свидетельствуют о важной роли гена TGFB1 в формировании предрасположенности к ИМ, в том числе к раннему и повторным ИМ.