Genetic Risk Factors for Adverse Drug Reactions

The use of medicines may in some cases be associated with the development of drug-induced diseases (DIDs) аnd other adverse drug reactions (ADRs), which leads to an increase in morbidity/mortality rates, and/or symptoms forcing a patient to seek medical attention or resulting in hospitalisation. ADRs may develop due to changes in a patient’s genotype, which entail an inadequate pharmacological response. The aim of the study was to analyse and summarise literature data on genetic risk factors that cause DIDs аnd other ADRs. It was shown that the polymorphism of genes encoding enzymes of drug metabolism (CYP, UGT, NAT, TPMT, EPHX, GST, etc.) or carriers (transporters) of drugs (P-gp, BCRP, MRP, OATP, OCT, etc.) can change the pharmacokinetics of drugs, affecting their activity. Polymorphism of RYR1, CACNA1S, MT-RNR1, VKORC1, and other genes encoding receptors targeted by drugs, and human leukocyte antigen (HLA) gene, may affect drug pharmacodynamics by modifying drug targets or changing the sensitivity of biological pathways to pharmacological effects of medicines. Changes in drug pharmacokinetics and pharmacodynamics may cause DIDs аnd other ADRs. The use of pharmacogenetic tests will allow a personalised approach to patients’ treatment and prevention or timely detection of potential ADRs during therapy. Before prescribing some medicines, clinicians should use recommendations on their dosing based on pharmacogenetic tests, which are posted on the official websites of Pharmacogenomics Research Network (PGRN), Pharmacogenomics Knowledgebase (PharmGKB), and Clinical Pharmacogenetics Implementation Consortium (CPIC). The results of ongoing clinical studies on the effect of gene polymorphism on drug safety will soon allow for higher personalisation of the choice of pharmacotherapy and prevention of many ADRs, including DIDs

РОЛЬ НАУЧНО-ИССЛЕДОВАТЕЛЬСКОГО ИНСТИТУТА ДЕТСКИХ ИНФЕКЦИЙ В РАЗВИТИИ ВАКЦИНОПРОФИЛАКТИКИ В РОССИИ (к 45-летию отдела «Профилактики инфекционных заболеваний»)

The results of the scientific, medical, organizational and methodological approaches, training of the “Prevention of Infectious Diseases” Research Institute for childhood infections aimed at achieving the main goal - raising children immunized and the resulting reduction in disease infections controllable mass immunization and disease prevention postvaccination period.Представлен результат научной, лечебной, организационно-методической, учебной деятельности отдела «Профилактика инфекционных болезней» ФГУ «Научно-исследовательский институт детских инфекций» ФМБА, направленный на достижение основной цели – повышение привитости детей и, как следствие, снижение заболеваемости инфекциями, управляемыми средствами иммунопрофилактики, а также на профилактику заболеваний поствакцинального периода

Studies to elucidate the effect and antiapoptotic mechanism of 2-ethyl-3-hydroxy-6- methylpyridine-n-acetyltaurinate in a rat model of retinal ischemia-reperfusion

To study the retinoprotective effect and antiapoptotic mechanism of 2-Ethyl-3-hydroxy-6-methyl-pyridine-Nacetyltaurinate (EHMP-NAT) in a rat model of retinal ischemia-reperfusio

Comparative analysis of allele frequencies for DNA polymorphisms associated with disease and economically important traits in the genomes of Russian and foreign cattle breeds

The genetic makeup of a breed including its genetic differences from other breeds determines its appearance and characteristics, including economically important traits and resistance to pathologies. To date, many loci controlling significant phenotypes have been identified, which is successfully used in the world practice of marker-assisted selection to improve breed properties. The aim of this study was a comparative analysis of frequencies for known causative nucleotide substitutions, insertions and deletions associated with disease and economically important traits in Russian and foreign cattle breeds. As a result, we identified frequencies of these DNA polymorphisms in the populations of Russian cattle breeds, compared them with those of foreign populations of the same breed, as well as other foreign breeds. Our results indicate similarities in frequencies for most of such alleles within breeds (populations of Russian and foreign breeding), as well as the relationship between the causative allele prevalence and the presence of phenotypic traits under the effect. We also found an excess of some undesirable alleles in the Russian cattle populations, which should be paid attention to when designing breeding programs. We found that the alleles increasing fertility in the Hereford breed have a higher frequency in the Russian Hereford population compared to the foreign counterpart. Interestingly, unlike for the European breeds, for Asian Turano-Mongolian Wagyu and Yakut cattle, there was a less clear link between phenotypic traits and frequencies of known causative alleles. Our work points to specific genetic variants that could be used to improve and/or maintain the performance of certain cattle breeds bred in the Russian Federation

Contrasting origin of B chromosomes in two cervids (Siberian roe deer and grey brocket deer) unravelled by chromosome-specific DNA sequencing

Abstract Background B chromosomes are dispensable and variable karyotypic elements found in some species of animals, plants and fungi. They often originate from duplications and translocations of host genomic regions or result from hybridization. In most species, little is known about their DNA content. Here we perform high-throughput sequencing and analysis of B chromosomes of roe deer and brocket deer, the only representatives of Cetartiodactyla known to have B chromosomes. Results In this study we developed an approach to identify genomic regions present on chromosomes by high-throughput sequencing of DNA generated from flow-sorted chromosomes using degenerate-oligonucleotide-primed PCR. Application of this method on small cattle autosomes revealed a previously described KIT gene region translocation associated with colour sidedness. Implementing this approach to B chromosomes from two cervid species, Siberian roe deer (Capreolus pygargus) and grey brocket deer (Mazama gouazoubira), revealed dramatically different genetic content: roe deer B chromosomes consisted of two duplicated genomic regions (a total of 1.42-1.98 Mbp) involving three genes, while grey brocket deer B chromosomes contained 26 duplicated regions (a total of 8.28-9.31 Mbp) with 34 complete and 21 partial genes, including KIT and RET protooncogenes, previously found on supernumerary chromosomes in canids. Sequence variation analysis of roe deer B chromosomes revealed a high frequency of mutations and increased heterozygosity due to either amplification within B chromosomes or divergence between different Bs. In contrast, grey brocket deer B chromosomes were found to be more homogeneous and resembled autosomes in patterns of sequence variation. Similar tendencies were observed in repetitive DNA composition. Conclusions Our data demonstrate independent origins of B chromosomes in the grey brocket and roe deer. We hypothesize that the B chromosomes of these two cervid species represent different stages of B chromosome sequences evolution: probably nascent and similar to autosomal copies in brocket deer, highly derived in roe deer. Based on the presence of the same orthologous protooncogenes in canids and brocket deer Bs we argue that genomic regions involved in B chromosome formation are not random. In addition, our approach is also applicable to the characterization of other evolutionary and clinical rearrangements

ЭНЕРГОДЕФИЦИТ ТРОМБОЦИТОВ У БОЛЬНЫХ С ОСТРЫМ КОРОНАРНЫМ СИНДРОМОМ В СОЧЕТАНИИ С ТРЕВОЖНО-ДЕПРЕССИВНЫМИ РАССТРОЙСТВАМИ

Purpose. We study of enzyme activity of blood platelets in patients with acute coronary syndrome (ACS) in a combination with anxiety and depressive disorders (ADD ).Materials and methods. We examined 315 patients of both sexes in the first 24 hours of the ACS. There were 154 ACS patients without ADD and 161 patients with ADD . We researched the activity of the NAD and NADP-dependent dehydrogenases in platelets of the patients using bioluminescence assay methods in the first 24 hours after the patients’ admission and in the disease progress on the 10th day.Results. A distinctive feature of the platelet metabolism in patients with ACS without ADD is a decreased level of aerobic respiration activity accompanied with the violation of interrelation between the Krebs cycle and reactions of amino acid metabolism while anaerobic respiration intensity is at a normal level. Patients who had ACS with ADD at all the stages of the examination had decreased activity of both anaerobic and aerobic respiration beside the disrupted connection between the products of amino acid metabolism and the Krebs cycle reactions.Conclusion. ACS patients with ADD had a more pronounced change in the platelet energy metabolism, which may be one of the pathophysiological causes of the violation of the functional platelet activity in the hemostasis.Цель. Изучение активности ферментов тромбоцитов у больных с острым коронарным синдромом (ОКС) в сочетании с тревожно-депрессивными расстройствами (ТД Р).Материалы и методы. Обследовано 315 пациентов обоего пола в первые 24 часа от развития острого коронарного синдрома. Были сформированы две группы: первая – больные с ОКС с ТД Р (n=161) и вторая – больные с ОКС без ТД Р (n=154). В первые 24 часа после госпитализации пациентов и в динамике заболевания на 10-е сутки с помощью методов биолюминесцентного анализа проведено исследование активности НАД- и НАДФ-зависимых дегидрогеназ в тромбоцитах больных.Результаты. У больных с ОКС без ТД Р выявлено снижение уровня активности аэробного дыхания на фоне нарушения взаимосвязи цикла Кребса с реакциями аминокислотного обмена, но при сохранении нормального уровня интенсивности анаэробного дыхания. У больных с ОКС с ТД Р на всех этапах обследования выявлено снижение активности анаэробного и аэробного дыхания на фоне сниженного переноса продуктов аминокислотного обмена на реакции цикла Кребса.Выводы. Таким образом, у больных с ОКС с ТД Р выявлено более выраженное изменение энергометаболизма, что может являться одной из патофизиологических причин нарушения функциональной активности тромбоцитов в процессах гемостаза

Contrasting origin of B chromosomes in two cervids (Siberian roe deer and grey brocket deer) unravelled by chromosome-specific DNA sequencing.

BACKGROUND: B chromosomes are dispensable and variable karyotypic elements found in some species of animals, plants and fungi. They often originate from duplications and translocations of host genomic regions or result from hybridization. In most species, little is known about their DNA content. Here we perform high-throughput sequencing and analysis of B chromosomes of roe deer and brocket deer, the only representatives of Cetartiodactyla known to have B chromosomes. RESULTS: In this study we developed an approach to identify genomic regions present on chromosomes by high-throughput sequencing of DNA generated from flow-sorted chromosomes using degenerate-oligonucleotide-primed PCR. Application of this method on small cattle autosomes revealed a previously described KIT gene region translocation associated with colour sidedness. Implementing this approach to B chromosomes from two cervid species, Siberian roe deer (Capreolus pygargus) and grey brocket deer (Mazama gouazoubira), revealed dramatically different genetic content: roe deer B chromosomes consisted of two duplicated genomic regions (a total of 1.42-1.98 Mbp) involving three genes, while grey brocket deer B chromosomes contained 26 duplicated regions (a total of 8.28-9.31 Mbp) with 34 complete and 21 partial genes, including KIT and RET protooncogenes, previously found on supernumerary chromosomes in canids. Sequence variation analysis of roe deer B chromosomes revealed a high frequency of mutations and increased heterozygosity due to either amplification within B chromosomes or divergence between different Bs. In contrast, grey brocket deer B chromosomes were found to be more homogeneous and resembled autosomes in patterns of sequence variation. Similar tendencies were observed in repetitive DNA composition. CONCLUSIONS: Our data demonstrate independent origins of B chromosomes in the grey brocket and roe deer. We hypothesize that the B chromosomes of these two cervid species represent different stages of B chromosome sequences evolution: probably nascent and similar to autosomal copies in brocket deer, highly derived in roe deer. Based on the presence of the same orthologous protooncogenes in canids and brocket deer Bs we argue that genomic regions involved in B chromosome formation are not random. In addition, our approach is also applicable to the characterization of other evolutionary and clinical rearrangements

Drug-Induced Atrial Fibrillation / Atrial Flutter

Drug-induced atrial fibrillation / flutter (DIAF) is a serious and potentially life-threatening complication of pharmacotherapy. Purpose of the work: systematization and analysis of scientific literature data on drugs, the use of which can cause the development of DIAF, as well as on epidemiology, pathophysiological mechanisms, risk factors, clinical picture, diagnosis and differential diagnosis, treatment and prevention of DIAF. Analysis of the literature has shown that many groups of drugs can cause the development of DIAF, with a greater frequency while taking anticancer drugs, drugs for the treatment of the cardiovascular, bronchopulmonary and central nervous systems. The mechanisms and main risk factors for the development of DIAF have not been finally established and are known only for certain drugs, therefore, this section requires further study. The main symptoms of DIAF are due to the severity of tachycardia and their influence on the parameters of central hemodynamics. For diagnosis, it is necessary to conduct an electrocardiogram (ECG) and Holter monitoring of an ECG and echocardiography. Differential diagnosis should be made with AF, which may be caused by other causes, as well as other rhythm and conduction disturbances. Successful treatment of DIAF is based on the principle of rapid recognition and immediate discontinuation of drugs (if possible), the use of which potentially caused the development of adverse drug reactions (ADR). The choice of management strategy: heart rate control or rhythm control, as well as the method of achievement (medication or non-medication), depends on the specific clinical situation. For the prevention of DIAF, it is necessary to instruct patients about possible symptoms and recommend self-monitoring of the pulse. It is important for practitioners to be wary of the risk of DIAF due to the variety of drugs that can potentially cause this ADR

Genome-Wide Mycobacterium tuberculosis Variation (GMTV) Database: A New Tool for Integrating Sequence Variations and Epidemiology

Background Tuberculosis (TB) poses a worldwide threat due to advancing multidrug-resistant strains and deadly co-infections with Human immunodeficiency virus. Today large amounts of Mycobacterium tuberculosis whole genome sequencing data are being assessed broadly and yet there exists no comprehensive online resource that connects M. tuberculosis genome variants with geographic origin, with drug resistance or with clinical outcome. Description Here we describe a broadly inclusive unifying Genome-wide Mycobacterium tuberculosis Variation (GMTV) database, (http://mtb.dobzhanskycenter.org) that catalogues genome variations of M. tuberculosis strains collected across Russia. GMTV contains a broad spectrum of data derived from different sources and related to M. tuberculosis molecular biology, epidemiology, TB clinical outcome, year and place of isolation, drug resistance profiles and displays the variants across the genome using a dedicated genome browser. GMTV database, which includes 1084 genomes and over 69,000 SNP or Indel variants, can be queried about M. tuberculosis genome variation and putative associations with drug resistance, geographical origin, and clinical stages and outcomes. Conclusions Implementation of GMTV tracks the pattern of changes of M. tuberculosis strains in different geographical areas, facilitates disease gene discoveries associated with drug resistance or different clinical sequelae, and automates comparative genomic analyses among M. tuberculosis strains