Ожирение становится одной из глобальных проблем – более трети мирового населения имеют избыточный вес. Эта патология существенно влияет на качество жизни и является фактором риска сердечно-сосудистых заболеваний, сахарного диабета, рака и нарушений репродуктивной функции. Нами изучена популяционная вариабельность частот аллелей 26 однонуклеотидных полиморфных маркеров, ассоциированных с ожирением и индексом массы тела по данным полногеномных ассоциативных исследований (GWAS). Генетическая изменчивость проанализирована в популяциях Северной Евразии и популяциях из проекта по изучению разнообразия генома человека (HGDP). Исследованные этнические группы характеризуются высоким уровнем генетического разнообразия, которое коррелирует с климато-географическими параметрами. Результаты тестов на поиск сигналов естественного отбора свидетельствуют о действии отбора на маркеры rs1167827 гена HIP1, rs7138803 и rs7164727, расположенные в межгенной области, rs7141420 гена NRXN3, rs7498665 гена SH2B1, rs7903146 гена TCF7L2.

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age (“early MI” denoting individuals who had the first MI before the age of 60 years, and “late MI” the group of patients with the first “MI after 60 years”). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 (“StatSoft Inc.”, USA), as well as the “stats” and “genetics” packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23‒3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23‒4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11‒2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).

Цель исследования заключалась в выявлении особенностей генетической структуры подверженности инфаркту миокарда (ИМ) в зависимости от возраста пациентов. Всего обследовано 355 пациентов (n = 121, ранний ИМ ‒ индивиды, у которых первый ИМ зарегистрирован в возрасте до 60 лет; и n = 234 c первым ИМ в возрасте старше 60 лет) и 285 жителей Сибирского региона (контрольная группа). Генотипирование 58 однонуклеотидных вариантов (SNP) выполнено с помощью MALDITOF масс-спектрометрии. Регуляторный потенциал SNP оценивали с помощью онлайн сервисов (http://rsnp.psych.ac.cn/; http://www.gtexportal.org/; https://genenetwork.nl/bloodeqtlbrowser/). Генотипы GG rs1143674 гена ITGA4, СС rs1333049 гена CDKN2B-AS1 и СС rs3739998 гена KIAA1462 ассоциированы с ИМ в общей группе больных. Генотипы АА гена ADAMDEC1 (OR = 2.03; 95% CI 1.23‒3.33; p = 0.004) и GG rs2878771 гена AQP2 (OR = 2.24; 95% CI 1.23‒4.09; p = 0.006) связаны с развитием ИМ в раннем возрасте, а генотип ТТ гена TAS2R38 (OR = 1.82; 95% CI 1.11‒2.89; p = 0.009) был фактором риска первого ИМ, произошедшего после 60 лет. Генетические варианты, ассоциированные с ИМ, относятся к регуляторным (rSNP): влияют на аффинность связывания ДНК с транскрипционными факторами, вовлечены в посттранскрипционный контроль генной активности и модулируют уровень экспрессии генов в различных тканях. Ранний и поздний ИМ имеют в своей основе как общие генетические варианты генов ITGA4, CDKN2B-AS1, KIAA1462, так и специфичные: ADAMDEC1 и AQP2 для раннего ИМ и TAS2R38 для ИМ, произошедшего после 60 лет.

Our previous studies have shown that BRCA1 gene deficiency caused by changes in the tumor such as low expression, deletion, loss of heterozygosity, etc., can be associated with the effectiveness of chemotherapy and the disease prognosis. However, even in the absence of these factors, the effectiveness of taxotere therapy was variable. This may be due to the availability of another BRCA1 gene somatic changes in the tumor tissue and their determination will help to define the personalize treatment strategy for each breast cancer patient. Here we investigated the entire spectrum germline and somatic mutation of coding region of the BRCA1 gene in tumor tissue. We obtained that absence of BRCA1 somatic mutation was associated with objective response on taxotere in the preoperative period. Germline mutations BRCA1: c.4837A>G (p.Ser1613Gly), c.999T>C (p.Ser333=), c.3548A>G (p.Lys1183Arg), c.3113A>G (p.Glu1038Gly), c.2612C>T (p.Pro871Leu), c.2311T>C (p.Leu771=), c.2082C>T (p.Ser694=) were associated with non-objective response on neoadjuvant chemotherapy (NAC), furthermore effect of chemotherapy was more than 80% without of these mutations. During chemotherapy, 13% of patients showed the appearance of 5 new BRCA1 mutations in the tumor and this is associated with a non-objective response to NAC by taxotere. Overall, our results suggest that it makes sense to take into account not only identified germline mutations, but also somatic changes in the BRCA1 gene when appointment taxotere

Hyperprolactinaemia, a common adverse effect of antipsychotic drugs, is primarily linked to blockade of dopamine D2 receptors in the pituitary gland. Certain antipsychotic drugs, such as, for example risperidone and paliperidone, are more likely to induce hyperprolactinaemia compared to others. This effect is probably caused by a relatively high blood/brain concentration ratio, a consequence of being a substrate of P-glycoprotein. Genetic variants of P-glycoprotein with changed functional activity might influence the potential of risperidone and paliperidone to cause hyperprolactinaemia as the altered blood/brain concentration ratio would lead to a reduced therapeutic drug level within essential brain areas making dose adaptations necessary. This increases exposure of dopamine D2 receptors within the pituitary gland.

The premalignant process preceding squamous cell lung cancer is not inevitable; it can stop at any of the bronchial lesions: basal cell hyperplasia (BCH), squamous metaplasia (SM), and dysplasia and then progress or regress. At present, the mechanisms underlying the progression of the bronchial lesions remain undefined. Previously, we hypothesized that bronchial lesions that presented individually or combined with each other in the bronchi of lung cancer patients mirror the different ""scenarios"" of the premalignant process: individual BCH-the stoppage at the stage of hyperplasia, BCH plus SM-the progression of hyperplasia to metaplasia, and SM plus dysplasia-the progression of metaplasia to dysplasia. In this study, we analyzed gene expression profiles of BCH, SM, and dysplasia depending on their cooccurrence in the bronchi of lung cancer patients. The immune response gene expression was found to be a key difference between the individual BCH and BCH combined with SM lesions and a potential mechanism that determines the progression of hyperplasia to metaplasia. Upregulation of the cell cycle and downregulation of the cilium assembly genes mainly distinguished SM that copresented with dysplasia from SM that copresented with BCH and is a probable mechanism of the progression of metaplasia to dysplasia. Dysplasia showed mainly overexpression of the cell division genes and underexpression of the inflammation genes. Thus, this study demonstrates the significant gene expression differences between the premalignant lesions depending on their cooccurrence in the bronchi and sheds light on the mechanisms of the precancerous process preceding squamous cell lung cancer.

Current definitions of metabolic syndrome give no idea of the origin and metabolic essence of this medical condition. We have provided arguments that from the point of view of the human post-embryonic ontogenesis, MetS may represent metabolic features of the post-reproductive stage of ontogenesis. At this stage, sexual hormones diminish their influence and energy metabolism in men and women becomes based on predominant utilization of fats and proteins. This proposition is confirmed by the facts that the menopause increases incidence of MetS in aging women. Moreover, in younger women, surgical menopause is strongly linked with a higher incidence of MetS [50]. Because the pressure of natural selection on the post-reproductive stage of ontogenesis was weak, the metabolic features at the post-reproductive stage resemble those of our distant ancestors. We suggest that major symptoms of MetS may originate from the mismatch between the genetically predetermined ancient metabolic pattern and the contemporary lifestyle with excessive consumption carbohydrates and insufficient physical activity of elderly people. Inclusion of ontogenesis into the mechanisms of aging and development of MetS might be helpful in finding pharmacological and non-pharmacological methods to slowdown development of these medical conditions.

Brugada syndrome (BrS) is an inherited disorder characterized by specific ST segment elevation in the right precordial leads, pseudo right bundle branch block, and a high risk of sudden cardiac death due to ventricular tachycardia. It was initially described as a monogenic disorder with an autosomal dominant mode of inheritance. It is hypothesized that modifying genetic factors, in addition to disease-causing mutations, may significantly contribute to the clinical symptoms and the risk of sudden cardiac death. These modifying factors can include mitochondrial DNA (mtDNA) variants. In particular, combination of mtDNA m.T4216C, m.A11251G, m.C15452A and m.T16126C variants (defining haplogroups T and J), is considered to be a factor that promotes manifestation of BrS manifestation, with no pro-arrhythmic effects. The aim of the present study was to confirm the reported association of BrS with MtDNA variants in a cohort of Russian patients. mtDNA haplogroups were genotyped in 47 Russian BrS probands and the prevalence of common mtDNA haplogroups was compared with the general population in European part of Russia. The distribution and prevalence of all but the J mtDNA haplogroups were comparable in BrS probands and the general Russian population. The mitochondrial J haplogroup was not found in the BrS cohort. In conclusion, it was shown that the mtDNA polymorphism, m.T4216C (haplogroups J and T) does not contribute significantly to the clinical manifestation of BrS in Russian patients.

Chromosomal microdeletion syndromes present with a wide spectrum of clinical phenotypes that depend on the size and gene content of the affected region. In a healthy carrier, epigenetic mechanisms may compensate for the same microdeletion, which may segregate through several generations without any clinical symptoms until the epigenetic modifications no longer function. We report 2 novel cases of Xq24 microdeletions inherited from mothers with extremely skewed X-chromosome inactivation (sXCI). The first case is a boy presenting with X-linked mental retardation, Nascimento type, due to a 168-kb Xq24 microdeletion involving 5 genes (CXorf56, UBE2A, NKRF, SEPT6, and MIR766) inherited from a healthy mother and grandmother with sXCI. In the second family, the presence of a 239-kb Xq24 microdeletion involving 3 additional genes (SLC25A43, SLC25A5-AS1, and SLC25A5) was detected in a woman with sXCI and a history of recurrent pregnancy loss with a maternal family history without reproductive wastages or products of conception. These cases provide evidence that women with an Xq24 microdeletion and sXCI may be at risk for having a child with intellectual disability or for experiencing a pregnancy loss due to the ontogenetic pleiotropy of a chromosomal microdeletion and its incomplete penetrance modified by sXCI.

Cell models are promising tools for studying hereditary human neurodegenerative diseases. Neuronal derivatives of pluripotent stem cells provide the opportunity to investigate different stages of the neurodegeneration process. Therefore, easy and large-scale production of relevant cell types is a crucial barrier to overcome. In this work, we present an alternative protocol for iPSC differentiation into GABAergic medium spiny neurons (MSNs). The first stage involved dual-SMAD signalling inhibition through treatment with SB431542 and LDN193189, which results in the generation of neuroectodermal cells. Moreover, we used bFGF as a neuronal survival factor and dorsomorphin to inhibit BMP signalling. The combined treatment of dorsomorphin and SB431542 significantly enhanced neuronal induction, which was confirmed by the increased expression of the telencephalic-specific markers SOX1 and OTX2 as well as the forebrain marker PAX6. The next stage involved the derivation of actively proliferating MSN progenitor cells. An important feature of our protocol at this stage is the ability to perform prolonged cultivation of precursor cells at a high density without losing phenotypic properties. Moreover, the protocol enables multiple expansion steps (> 180 days cultivation) and cryopreservation of MSN progenitors. Therefore, this method allows quick production of a large number of neurons that are relevant for basic research, large-scale drug screening, and toxicological studies.

Mannose-binding lectin (MBL) encoded by MBL2 gene is a protein with the ability to form carbohydrate complexes with microbial wall promoting their subsequent elimination. Genetically determined levels of MBL can modify the risk and clinical characteristics of many infectious diseases. The frequency of MBL2 genotypes exhibits significant population differences. The data on the distribution of MBL2 genotypes among the aborigines of the Russian Arctic territories have not yet been published. A total of 880 specimens of dried blood spots of the newborns were genotyped. The newborns represented four populations: Nenets, Dolgan-Nganasans, Mixed aboriginal population, and Russians (Caucasians, Krasnoyarsk). Six polymorphisms of the MBL2 gene were studied: rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, and rs1800451. The frequency of the combined rare O allele (composed of the coding region variants rs5030737, rs1800450, and rs1800451) in the homozygous state was significantly higher in Russians: 10% vs 2% in Nenets and 1% in Dolgan-Nganosans (p < 0.001 for Russians vs other populations). The frequency of the high-producing haplotype (HYPA) was 35.4% in the Russian newborns, in keeping with European populations (27-33%); 64% for Nenets and 56% for Dolgan-Nganasans, similar to the estimates obtained for Eskimos and North Amerinds (64-81%). Our study results are in line with the hypothesis that human evolution has been moving in the direction of accumulation of the genotypes associated with low activity of the lectin complement activation pathway because of the prevalence of some intracellular infections such as tuberculosis, whereby low MBL activity may have a protective effect.

Noninvasive prenatal testing (NIPT) using cell-free fetal DNA has increasingly been adopted as a screening tool for fetal aneuploidies. Several studies have discussed benefits and limitations of NIPT compared with both ultrasound and invasive procedures, but in spite of some shortcomings NIPT has become extensively used within the last 5 years. This study aims to describe the current use of NIPT in Europe, Australia and the USA.

Purpose: To study the contribution of embryo chromosomal abnormalities in primary and secondary recurrent pregnancy loss (RPL) and to analyze the recurrence of chromosomal constitution in miscarriages from the same couple.

Methods: Retrospective study of abortion karyotypes in RPL families based on the mother's primary or secondary RPL status (563 embryo specimens, 335 samples from primary, and 228 samples from secondary RPL). RPL was defined as two or more consecutive miscarriages. One hundred eight cases of recurrent embryo/fetal loss in 51 families were analyzed to assess the probability of having the same karyotype pattern (recurrent normal or recurrent abnormal) in both previous and subsequent pregnancy loss. The karyotypes of abortions were established using standard cytogenetic analysis, as well as interphase fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH).

Results: The frequency of aberrations was 43.9% in abortions from primary RPL versus 52.6% in secondary RPL (p = 0.041). Women 35 years of age or older were the main contributors to this difference. The odds ratio of a subsequent abortion having the same karyotype pattern (normal or abnormal) as the previous one was 6.98 (p = 0.0013).

Ring chromosome 8 (r(8)) is one of the least frequent ring chromosomes. Usually, maternal chromosome 8 forms a ring, which can be lost from cells due to mitotic instability. The 8q24 region contains the imprinted KCNK9 gene, which is expressed from the maternal allele. Heterozygous KCNK9 mutations are associated with the imprinting disorder Birk-Barel syndrome. Here, we report a 2.5-year-old boy with developmental delay, microcephaly, dysmorphic features, diffuse muscle hypotonia, feeding problems, motor alalia and noncoarse neurogenic type of disturbance of muscle electrogenesis, partially overlapping with Birk-Barel syndrome phenotype. Cytogenetic analysis of lymphocytes revealed his karyotype to be 46,XY,r(8)(p23q24.3)[27]/45,XY,-8[3]. A de novo 7.9 Mb terminal 8p23.3p23.1 deletion, a 27.1 Mb 8p23.1p11.22 duplication, and a 4.4 Mb intact segment with a normal copy number located between them, as well as a 154-kb maternal LINGO2 gene deletion (9p21.2) with unknown clinical significance were identified by aCGH + SNP array. These aberrations were confirmed by real-time PCR. According to FISH analysis, the 8p23.1-p11.22 duplication was inverted. The ring chromosome originated from maternal chromosome 8. Targeted massive parallel sequencing did not reveal the KCNK9 mutations associated with Birk-Barel syndrome. Our data allow to assume that autosomal monosomy with inactive allele of imprinted gene arising from the loss of a ring chromosome in some somatic cells may be an etiological mechanism of mosaic imprinting disorders, presumably with less severe phenotype.

Genome stability is an integral feature of all living organisms. Aneuploidy is the most common cause of fetal death in humans. The timing of bursts in increased aneuploidy frequency coincides with the waves of global epigenetic reprogramming in mammals. During gametogenesis and early embryogenesis, parental genomes undergo two waves of DNA methylation reprogramming. Failure of these processes can critically affect genome stability, including chromosome segregation during cell division. Abnormal methylation due to errors in the reprogramming process can potentially lead to aneuploidy. On the other hand, the presence of an entire additional chromosome, or chromosome loss, can affect the global genome methylation level. The associations of these two phenomena are well studied in the context of carcinogenesis, but here, we consider the relationship of DNA methylation and aneuploidy in early human and mammalian ontogenesis. In this review, we link these two phenomena and highlight the critical ontogenesis periods and genome regions that play a significant role in human reproduction and in the formation of pathological phenotypes in newborns with chromosomal aneuploidy.