Analysis of association of allergic rhinitis with the KCNE4 gene rs12621643 variant was conducted in Russian residents of West Siberia (taking into account comorbidity with bronchial asthma). It was found that, among individuals without bronchial asthma, the frequencies of the KCNE4*G allele and KCNE4*G/G genotype are significantly higher in patients with rhinitis compared to individuals without it. At the same time, no association of rs12621643 with rhinitis was detected in the group of individuals with bronchial asthma. The data obtained indicate the association of the KCNE4 gene variability with allergic rhinitis, although the effect of this gene relative to the development of the disease can be leveled against a background of the manifestation of another atopic disease.

Проведен анализ связи аллергического ринита с вариантом rs12621643 гена KCNE4 у русских жителей Западной Сибири с учетом коморбидности с бронхиальной астмой. Установлено, что среди лиц, не имеющих бронхиальной астмы, частоты аллеля KCNE4*G и генотипа KCNE4*G/G статистически значимо выше у больных ринитом по сравнению с лицами без этого заболевания. В то же время не найдена ассоциация rs12621643 с ринитом в группе лиц, страдающих бронхиальной астмой. Полученные данные свидетельствуют о связи изменчивости гена KCNE4 с аллергическим ринитом, хотя эффект этого гена в отношении развития заболевания может быть нивелирован на фоне манифестации другого атопического заболевания.

The gene-pool structure of Tuvinians was examined in terms of the composition and frequency of Y-chromosome haplogroups in five geographically distanct populations. In the Tuvinian gene pool, a total of 22 haplogroups were identified with six of these, which were the most frequent (C3c, C3*, N1b, N1c1, Q1a3, and R1a1a). It was demonstrated that eastern regions of Tuva were most different from the other regions in haplotype frequencies. The evaluation of genetic diversity based on the frequencies of biallelic haplogroups and YSTR haplotypes revealed very high diversity values for all samples. In general, the genetic diversity values identified in Tuvinians were the highest for the indigenous ethnic groups of Siberia. The evaluation of the genetic differentiation of the samples examined using the analysis of molecular variance (AMOVA) showed that the gene pool of Tuvinians was relatively poorly differentiated with respect to haplogroup frequencies. Phylogenetic analysis within haplogroup N1b revealed strong founder effect, i.e., reduced diversity and star-like phylogeny of the median network of haplotypes, which formed a separate subcluster exclusive to Tuvinians. It was demonstrated that, in Tuvinians, haplogroup N1c1 was the most heterogeneous in haplotype profile and consisted of three different haplotype clusters, demonstrating considerable differences of western population from the rest of the Tuva populations. Phylogenetic analysis of haplogroups revealed common components for Tuvinians, Khakasses, Altaians, and Mongols.

Изучена структура генофонда тувинцев по составу и частоте гаплогрупп Y-хромосомы из пяти территориально дистанцированных популяций. В генофонде тувинцев обнаружено 22 гаплогруппы, шесть из которых являются наиболее частыми (С3с, С3*, N1b, N1c1, Q1а3 и R1a1а). По частотам гаплогрупп наибольшие отличия от остальных зафиксированы для восточных районов Тувы. Оценка генетического разнообразия на основании частот диаллельных гаплогрупп и YSTR-гаплотипов выявила очень высокие его значения для всех выборок. В целом тувинцы демонстрируют максимальные значения генетического разнообразия для коренных этносов Сибири. Оценка генетической дифференциации исследованных выборок с помощью анализа молекулярной дисперсии (AMOVA) показывает, что генофонд тувинцев относительно слабо дифференцирован по частотам гаплогрупп. Филогенетический анализ в пределах гаплогруппы N1b выявил сильный эффект основателя – пониженное разнообразие и “звездообразную” филогению медианной сети гаплотипов, образующих отдельный высокоспецифичный для тувинцев субкластер. Обнаружено, что гаплогруппа N1c1 у тувинцев по спектру гаплотипов наиболее гетерогенна и состоит из трех различных кластеров гаплотипов, демонстрируя значительные отличия западной популяции от остального населения Тувы. Результаты филогенетического анализа гаплогрупп выявили общие генетические компоненты у тувинцев с хакасами, алтайцами и монголами.

The frequency of the polymorphic variant T196C (Leu33Pro, rs5918) of ITGB3 gene was studied in several groups of inhabitants of Siberia, including women with reproductive disorders (n = 186), patients with acute coronary syndrome (n = 330), and population control (n = 858). The frequency of the rare PLA2 allele among residents of Tomsk and Kemerovo was 14.7% and 15.0% respectively. There were no differences in the allele and genotype frequencies of polymorphic variant between patients with acute coronary syndrome and the control group (p = 0.925, p = 0.622). The highest frequency of abnormal PLA2 allele (22.1%) and the PLA2/PLA2 genotype (8.8%) was observed among women who had miscarried, which was significantly different from the frequency of this allele and genotype in the control group (14.7%, p = 0.017; 2.1%, p = 0.0009). Sequencing showed that all samples with the nonspecific band had the polymorphic rs5918 variant and rs36080296 mutations (T216G, Leu66Arg). The frequency of the rs36080296 mutation among the residents of Siberia was 0.51%. Among the women with reproductive disorders, the frequency of rs36080296 was 2.7%, while in the group who suffered from miscarriages, it was 4.4%; this was different from the frequency in the control group (0.08%, p = 0.2 × 10−6). The accumulation of mutations was also observed among men with acute coronary syndrome (0.6%), but the differences from the control group (0%) had no statistical significance. Thus, the rs36080296 mutation may be a factor in predisposition to miscarriage, especially in combination with the PLAII allele. In addition, the rs36080296 variant among men may be associated with acute cor onary syndrome, which requires further study.

Изучена частота полиморфного варианта T196C (Leu33Pro, rs5918) гена ITGB3 у женщин с репродуктивными нарушениями, больных ишемической болезнью сердца с острым коронарным синдромом и в группе популяционного контроля. Частота редкого аллеля PLA2 у жителей г. Томска соответствовала 14.7%, г. Кемерово – 15.0%. Частота аллеля PLA2 (22.1%) и генотипа PLA2/PLA2 (8.8%) у женщин с невынашиванием беременности отличалась от контрольной группы (14.7%, р = 0.017; 2.1%, р = 0.0009). Секвенирование выявило мутацию rs36080296 (T216G, Leu66Arg), частота которой у женщин с репродуктивными нарушениями достигала 2.7%; в группе с невынашиванием беременности – 4.4%, что значимо отличалось от контроля (0.08%, р = 0.2 ? 10-6). Мутация rs36080296 может служить фактором, предрасполагающим к невынашиванию беременности, особенно в сочетании с аллелем PLA2.

Single-nucleotide polymorphisms (SNPs) in the 9p21.3 locus have recently been demonstrated to be strongly associated with atherosclerosis. However, the pathophysiology of this locus is insufficiently studied. Here, the methylation profile of the nearest mapped genes for cyclin-dependent kinase inhibitors CDKN2A (p16INK4a, p14ARF) and CDKN2B (p15INK4b) in the tissues of the carotid artery in patients with atherosclerosis was evaluated for the first time. Aberrant DNA methylation of the analyzed loci was not established in either the atherosclerotic plaques or in the tissues from the macroscopically intact vascular wall in the same patients.

Недавно была показана надежная ассоциация однонуклеотидных полиморфных вариантов (SNPs) региона 9p21.3 с риском развития заболеваний, в основе развития которых лежит атеросклеротическое поражение сосудистой стенки. Однако патофизиология данного локуса изучена недостаточно. В настоящем исследовании впервые оценен профиль метилирования ближайших картированных генов ингибиторов циклин-зависимых киназ CDKN2A (p16INK4a и p14ARF) и CDKN2B (p15INK4b) в тканях сонных артерий у больных атеросклерозом. В результате не выявлено аберрантного метилирования ДНК анализируемых участков генов в тканях из области атеросклеротических бляшек и предлежащей макроскопически неизмененной сосудистой стенки у тех же самых больных.

Life span depends on many factors, including the level of reactive oxygen species, like superoxide radical. Superoxide radical is produced from oxygen in the course of the oxidation of NADPH to NADP+. The process is catalyzed by NADPH oxidase. In this study, genotype and allele distributions of the C242T (rs4673) polymorphism in the CYBA gene, which encodes the α subunit of NADPH oxidase (p22phox), were examined in the sample of long livers and in the population sample of the city of Tomsk. Statistically significantly higher frequency of T allele among female long livers (34.625%), compared to the females from Russian population (26.32%) was demonstrated (χ2 = 5.226; p = 0.022; OR = 1.48). Thus, the T allele is associated with a high life expectancy in females from the Russian population. No such association was observed for males from the same population.

Продолжительность жизни зависит от многих факторов, в том числе от уровня продукции активных форм кислорода, таких как супероксид-радикал. Супероксидный радикал образуется из кислорода в процессе реакции окисления НАДФН до НАДФ+, катализируемой ферментом НАДФН-оксидазой. В данном исследовании проанализировано распределение генотипов и аллелей полиморфного варианта C242T (rs 4673) гена CYBA, кодирующего -субъединицу НАДФН-оксидазы (p22phox), в выборке долгожителей и в популяционной выборке жителей г. Томска. Выявлена статистически значимо более высокая частота аллеля Т у женщин-долгожителей – 34.62% по сравнению с женщинами из популяционной выборки – 26.32% ( 2 = 5.226; р = 0.022, OR = 1.48). Таким образом, аллель Т ассоциирован с высокой продолжительностью жизни у женщин в российской популяции. Для мужчин подобной ассоциации не выявлено.

Invasive ductal carcinoma (IDC) not otherwise specified (NOS), the most common type of breast cancer, demonstrates great intratumoral morphological heterogeneity, which encompasses the presence of different types of morphological structures-tubular, trabecular, solid, and alveolar structures and discrete groups of tumor cells, the origins of which remain unclear at present. In this study of 162 IDC NOS patients, we investigated whether the distribution of different types of morphological structures is related to the basic clinicopathological parameters of IDC NOS. Our results showed that in patients with only one type of tumor structure, the presence of any one of the five types was equally probable; however, cases with two types of structures were more likely to contain trabecular structures than the other four types. The development of intratumoral morphological heterogeneity was not associated with menopausal status, tumor size, histological grade, hematogenic metastasis, or recurrence. However, the number of different types of morphological structures was significantly higher in luminal tumors than in triple-negative tumors. An increase in the frequency of lymph node metastasis correlated with the increased number of different types of structures in breast tumors; however, in contrast to premenopausal patients, this association was explained by the presence of alveolar structures in postmenopausal women. In addition, we showed a significant decrease in the numbers of positive lymph nodes in tumors with high numbers of morphological variants. The frequency of lymph node metastases and the number of positive nodes were generally independent features and formed by different mechanisms. Based on the evidence, the term ""phenotypic drift"" has been designated as the basis for the development of intratumoral morphological heterogeneity of IDC NOS.

Abstract Purpose: Human hematopoietic stem cells (HSC) are thought to be a major target of radiation-induced leukemogenesis and also provide a relevant cellular model for assessing cancer risk. Cluster of designation 133+ (CD133+) is a marker found in human progenitor and hematopoietic stem cells. Our study examined the repair of radiation-induced DNA double-strand breaks (DSB) in CD133 + umbilical cord blood cells (UCBC).

Materials and methods: After γ-irradiation, endogenous and induced DSB were evaluated in CD133 + UCBC, CD133 - UCBC and peripheral blood lymphocytes (PBL) in terms of phosphorylated histone 2A family member X (γH2AX) and tumor suppressor p53 binding protein 1 (53BP1) foci.

Results: We found that repair signaling in CD133 + UCBC is different from CD133 - UCBC and PBL. These differences include lower endogenous DSB levels and higher 53BP1 recruitment.

Conclusions: Our data, together with a recent report on radiation-induced γH2AX and 53BP1 foci in CD34 + cells, indicate enhanced DNA repair capacity in HSC as compared to mature lymphocytes.

Moldova has a rich historical and cultural heritage, which may be reflected in the current genetic makeup of its population. To date, no comprehensive studies exist about the population genetic structure of modern Moldavians. To bridge this gap with respect to paternal lineages, we analyzed 37 binary and 17 multiallelic (STRs) polymorphisms on the non-recombining portion of the Y chromosome in 125 Moldavian males. In addition, 53 Ukrainians from eastern Moldova and 54 Romanians from the neighboring eastern Romania were typed using the same set of markers. In Moldavians, 19 Y chromosome haplogroups were identified, the most common being I-M423 (20.8%), R-M17* (17.6%), R-M458 (12.8%), E-v13 (8.8%), R-M269* and R-M412* (both 7.2%). In Romanians, 14 haplogroups were found including I-M423 (40.7%), R-M17* (16.7%), R-M405 (7.4%), E-v13 and R-M412* (both 5.6%). In Ukrainians, 13 haplogroups were identified including R-M17 (34.0%), I-M423 (20.8%), R-M269* (9.4%), N-M178, R-M458 and R-M73 (each 5.7%). Our results show that a significant majority of the Moldavian paternal gene pool belongs to eastern/central European and Balkan/eastern Mediterranean Y lineages. Phylogenetic and AMOVA analyses based on Y-STR loci also revealed that Moldavians are close to both eastern/central European and Balkan-Carpathian populations. The data correlate well with historical accounts and geographical location of the region and thus allow to hypothesize that extant Moldavian paternal genetic lineages arose from extensive recent admixture between genetically autochthonous populations of the Balkan-Carpathian zone and neighboring Slavic groups.

A variety of hypotheses have been proposed to explain the association between trisomy and increasing maternal age in humans, virtually all of which assume that the underlying mechanisms involve meiotic errors. However, recently Hultén and colleagues [Hulten et al., 2010b] proposed a provocative model-the Oocyte Mosaicism Selection Model (OMSM)-that links age-dependent trisomy 21 to pre-meiotic errors in the ovary. Specifically, they propose that nondisjunctional events occur in a proportion of germ cells as they mitotically proliferate, resulting in mosaicism for trisomy 21. Assuming that the presence of an additional chromosome 21 delays meiotic progression, these cells would be ovulated later in reproductive life, resulting in an age-dependent increase in aneuploid eggs. Because this model has important clinical implications, we initiated studies to test it. We first analyzed oocytes from two trisomy 21 fetuses, combining immunostaining with FISH to determine the likelihood of detecting the additional chromosome 21 at different stages of meiosis. The detection of trisomy was enhanced during the earliest stage of prophase (leptotene), before homologs synapsed. Accordingly, in subsequent studies we examined the chromosome content of leptotene oocytes in seven second trimester female fetuses, analyzing three chromosomes commonly associated with human trisomies (i.e., 13, 16, and 21). In contrast to the prediction of the OMSM, we found no evidence of trisomy mosaicism for any chromosome. We conclude that errors in pre-meiotic germ cells are not a major contributor to human aneuploidy and do not provide an explanation for the age-related increase in trisomic conceptions.

Childhood asthma candidate gene PPP1R12B was identified in the first genomewide association study (GWAS) in Russians of west Siberia. Here, we report validation of this discovery in an independent cohort of Russians from the city of Kursk. Twenty-six single-nucleotide polymorphisms (SNP) in the gene were analysed, of which four were significantly associated with childhood asthma. Haplotypic structure of four markers was different in control and childhood asthma samples, implicating the importance of PPP1R12B haplotypes in predisposition to the disease. The haplotype comprising common alleles was protective against asthma, while other haplotypes were positively associated with the disease. We propose possible mechanisms of the association, including impact of the gene on airway hyperresponsiveness and C-C chemokine receptor 3 signalling pathway modulation.