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2017

Koroleva Yu.A., Nazarenko M.S., Kucher A.N.
Biochemistry (Moscow). 2017. 82(11), 1380-1390.
DOI: 10.1134/S0006297917110165

MicroRNAs are small non-coding single-strand RNAs that regulate gene expression. There are an increasing number of studies highlighting the important role of microRNAs in development and progression of cardiovascular diseases caused by atherosclerotic lesions of arteries. Here we review the available data on the association of microRNA expression with instability of atherosclerotic plaques in model animals and in humans. We emphasis data on miR-21, -100, -127, -133, -143/145, -221/222, and -494 because they were analyzed in more than one study. We discuss the possibility of using microRNAs in diagnosis and therapy of atherosclerosis and its complications.

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Kucher A.N., Nazarenko M.S., Markov A.V., Koroleva I.A., Barbarash O.L.
Biochemistry (Moscow). 2017. 82(6), 698-706.
DOI: 10.1134/S0006297917060062

In this study, we for the first time described the variability of methylation levels of 71 CpG sites in microRNA genes in leukocytes and blood vessels (coronary artery atherosclerotic plaques, intact internal thoracic arteries, and great saphenous veins) in patients with atherosclerosis using the Infinium HumanMethylation27 BeadChip microarray. Most of the analyzed CpG sites were characterized by the low variability, and most of these low-variable sites were hypomethylated in all tissue samples. CpG sites in coronary artery atherosclerotic plaques and leukocytes were similar in their methylation status. The highest variability of CpG methylation levels between different tissues was found for the CpG sites of the MIR10B gene; the methylation levels of these sites in leukocytes and atherosclerotic arteries were lower than in intact blood vessels. We also found that several cardiovascular disease risk factors, as well as medications, might affect methylation levels of CpG sites in microRNAs.

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Кучер А.Н., Назаренко М.С., Марков А.В., Королёва Ю.А., Барбараш О.Л.
Биохимия. 2017. Т. 82. № 6. С. 923-933

В настоящем исследовании впервые охарактеризована вариабельность уровней метилирования 71 CpG-сайта генов микроРНК в лейкоцитах крови и тканях сосудов (область атеросклеротических бляшек коронарных артерий, морфологически неизмененные внутренние грудные артерии и большие подкожные вены) у больных атеросклерозом (использованы данные с микрочипа Infinium Human Methylation27 BeadChip). Установлено, что для большинства изученных CpG-сайтов генов микроРНК характерна незначительная вариабельность метилирования, среди них преобладают CpG-сайты с низким уровнем метилирования во всех образцах тканей. По уровню метилирования всех изученных CpG-сайтов генов микроРНК более близки между собой были ткани из области атеросклеротических бляшек коронарных артерий и лейкоциты крови. Наиболее высокая межтканевая вариабельность уровня метилирования установлена для CpG-сайтов гена MIR10B, причем в лейкоцитах и пораженных атеросклерозом артериях зарегистрирован более низкий уровень метилирования изученных CpG-сайтов по сравнению с непораженными тканями сосудов. Выявлена связь уровней метилирования CpG-сайтов генов микроРНК с некоторыми факторами риска сердечно-сосудистых заболеваний, а также приемом лекарственных препаратов.

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Belenko A.A., Vasilyev S.A., Lebedev I.N.
Russian Journal of Genetics: Applied Research. 2017. 7(2), 203–204.
DOI: 10.1134/S2079059717020034

The genotoxic effects of exposure to ionizing radiation during the early stages of human embryonic development can be fatal. Despite this, the radiosensitivity of human embryonic and differentiated extraembryonic cells is poorly studied. In this work, the efficiency of a DNA double-strand break repair in human extraembryonic fibroblasts was investigated. It was shown that the repair of radiation-induced DNA damage in human extraembryonic fibroblasts is likely to reflect the ability of these cells to repair spontaneous DNA double-strand breaks.

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Stepanov V.A., Kharkov V.N., Vagaitseva R.V., Bocharova A.V., Kazantsev A.Yu., Popovich A.A., Khitrinskaya I.Yu.
Russian Journal of Genetics. 2017. 53(11), 1172-1183.
DOI: 10.1134/S1022795417110114

Genetic diversity of native populations of North Eurasia is investigated using a panel of genetic markers of candidate genes for cold climate adaptation. A high level of within- and between-population variability is detected. Comparative analysis of data on North Eurasian populations combined with data on worldwide populations from the 1000 Genomes and HDGP projects reveals correlations of genetic diversity in candidate genes for cold climate adaptation with key climate parameters, as well as the increase of genetic diversity in markers of this group of genes with the increase of latitude, that is, as modern humans migrated out of Africa. Using the method of searching for extreme empirical values of the coefficient of genetic diversity, signals of directional selection for markers of six genes adaptive to cold (MYOF, LONP2, IFNL4, MKL1, SLC2A12, and CPT1A) are found. The data are discussed in framework of the hypothesis of decanalization of genome–phenome relationships under the pressure of natural selection during human settlement throughout the world.

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Степанов В.А., Харьков В.Н., Вагайцева К.В., Бочарова А.В., Казанцев А.Ю., Попович А.А., Хитринская И.Ю.
Генетика. 2017. Т. 53. № 11. С. 1254-1266
DOI: 10.7868/S0016675817110121

Исследовано генетическое разнообразие популяций коренного населения Северной Евразии по панели генетических маркеров кандидатных генов адаптации к холодному климату. Обнаружен высокий уровень внутрипопуляционного и межпопуляционного разнообразия в исследованных популяциях. Сравнительный анализ полученных данных с данными по мировым популяциям из проектов “1000 геномов” и HGDP выявил корреляции генетического разнообразия кандидатных генов адаптации к холодному климату с ключевыми климатическими характеристиками, а также обнаружил рост генетического разнообразия маркеров этой группы генов по мере удаления от экватора, т.е. в ходе расселения человека из Африки. Методом поиска крайних эмпирических значений коэффициента генетического разнообразия выявлены сигналы направленного отбора для маркеров шести генов адаптации к холоду - MYOF, LONP2, IFNL4, MKL1, SLC2A12 и CPT1A. Данные обсуждаются в рамках гипотезы деканализации геном-феномных отношений под действием естественного отбора в ходе расселения человека по территории земного шара.

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Tarasenko N.V., Goncharova I.A., Markov A.V., Kondrat’eva E.I.
Russian Journal of Genetics. 2017. 53(8), 923–929.
DOI: 10.1134/S1022795417070110

The genetic structure of susceptibility to type 1 diabetes (T1D) in the population of Tomsk was studied. We had a group of T1D patients (N = 285) and a population sample (N = 300) and we studied 58 SNPs localized in the 47 genes which products are involved in various metabolic pathways and processes as fibrogenesis, endothelial dysfunction, and inflammation. Genotyping was performed by mass spectrometry using the Sequenom MassARRAY system (United States). We compared the group of T1D patients and the population sample and found an association with the predisposition to disease for seven markers: rs3765124 of the ADAMDEC1 gene, genotype AA (p = 0.004), allele A (p = 0.033); rs1007856 of the ITGB5 gene, genotype TT (p = 0.015), allele T (p = 0.036); rs20579 of the LIG1 gene, genotype CC (p = 0.004), allele C (p = 0.002); rs12980602 of the IFNL2 gene, allele C (p = 0.029); rs4986819 of the PARP4 gene, allele C (p = 0.044); rs1143674 of the ITGA4 gene genotype GG (p = 0.002); rs679620 of the MMP3 gene, genotype AA (p = 0.008). Thus, the products of genes associated with T1D belong to different molecular classes: metalloproteases (ADAMDEC1, MMP3), cytokines (IL28A), cell surface receptors (ITGA4), adhesion molecules (ITGB5), DNA ligases (LIG1), and ribosyltransferase enzymes (PARP4). The ADAMDEC1, ITGA4, and ITGB5 genes belong to two biological processes: cell communication and signal transduction. The LIG1 and PARP4 genes regulate the metabolism of nucleic acids, MMP3 is involved in the regulation of protein metabolism, and the IFNL2 is involved in the immune response.

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Тарасенко Н.В., Гончарова И.А., Марков А.В., Кондратьева Е.И.
Генетика. 2017. Т. 53. № 8. С. 973-980.
DOI: 10.7868/S0016675817070116

В настоящей работе была исследована генетическая структура подверженности сахарного диабета 1-го типа (СД1) в популяции г. Томска. В группе больных СД1 (N = 285) и популяционной выборке (N = 300) изучено 58 однонуклеотидных полиморфизмов, локализованных в 47 генах, продукты которых участвуют в различных метаболических путях и вовлечены в процессы фиброгенеза, эндотелиальную дисфункцию, иммунный ответ и воспаление. Генотипирование выполнено методом масс-спектрометрии на приборе ""Sequenom MassARRAY"" (США). В результате выявлена ассоциация с СД1 для семи генетических маркеров: rs3765124 гена ADAMDEC1 генотип AA (р = 0.004) и аллель A (р = 0.033); rs1007856 гена ITGB5 генотип TT (р = 0.015) и аллель T (р = 0.036); rs20579 гена LIG1 генотип CC (р = 0.004) и аллель C (р = 0.002); rs12980602 гена IFNL2 аллель C (р = 0.029); rs4986819 гена PARP4 аллель C (р = 0.044); rs1143674 гена ITGA4 генотип GG (р = 0.002); rs679620 гена MMP3 генотип AA (р = 0.008). Продукты генов, для которых получена ассоциация с СД1, принадлежат к различным молекулярным классам: металлопротеазы (ADAMDEC1, MMP3), цитокины (IL28A), рецепторы клеточной мембраны (ITGA4), молекулы адгезии (ITGB5), ДНК-лигазы (LIG1), ферменты рибозилтрансферазы (PARP4). Гены ADAMDEC1, ITGA4, ITGB5 участвуют в двух биологических процессах: передаче сигнала и межклеточных взаимодействиях. Гены LIG1, PARP4 регулируют метаболизм нуклеиновых кислот, MMP3 вовлечен в регуляцию метаболизма белков, IFNL2 в иммунный ответ.

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Sazhenova E.A., Nikitina T.V., Skryabin N.A., Minaycheva L.I., Ivanova T.V., Nemtseva T.N. , Yuriev S.Yu., Evtushenko I.D., Lebedev I.N.
Russian Journal of Genetics. 2017. 53(3), 376-387.
DOI: 10.1134/S1022795417020090

An analysis of differential methylation of 47 imprinted genes in placenta tissues of spontaneous abortions at the first trimester of pregnancy from women with recurrent pregnancy loss or with one sporadic abortion was performed using the DNA-microarray approach. We showed that epimutations of the imprinted genes were registered significantly more often in abortions from women with recurrent miscarriage in contrast to the embryos from women with sporadic pregnancy loss with frequency of 6.2 and 3.7% per locus, respectively (p < 0.01). The predominant type of epimutation appeared to be a postzygotic hypomethylation of the imprinted genes on chromosomes of maternal origin, which was observed in the examined samples in 5.1 and 2.89% of cases, respectively. Replicative study of the methylation status of seven imprinted genes (DLK1, PEG10, PLAGL1, KCNQ1OT1, PEG3, GRB10, and PEG1/MEST) in the enlarged embryo samples supported the results of microarray analysis in respect to both epimutation frequency and predominance of somatic hypomethylation of maternal alleles. It was also demonstrated that pregnancy loss was associated with multilocus methylation defects of imprinted genes, the frequency of which was also significantly increased in the placental tissues of spontaneous abortions in women with recurrent miscarriage.

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Саженова Е.А., Никитина Т.В., Скрябин Н.А., Минайчева Л.И., Иванова Т.В., Немцева Т.Н., Юрьев С.Ю., Евтушенко И.Д., Лебедев И.Н.
Генетика. 2017. Т. 53. № 3. С. 364-377
DOI: 10.7868/S0016675817020096

В плацентарных тканях спонтанных абортусов I триместра беременности от женщин с привычным невынашиванием беременности или с одним спорадическим абортом с использованием ДНК-микрочипов проведен анализ дифференциального метилирования 47 импринтированных генов. Показано, что у абортусов от женщин с привычным невынашиванием беременности в отличие от эмбрионов от женщин со спорадической потерей беременности статистически значимо чаще регистрируются эпимутации импринтированных генов с частотой 6.2 и 3.7% на локус соответственно (р < 0.01). Преобладающим типом эпимутаций оказалось постзиготическое гипометилирование импринтированных генов на хромосомах материнского происхождения, составившее в исследованных группах 5.1 и 2.9% на локус соответственно. Репликативное исследование статуса метилирования семи импринтированных генов (DLK1, PEG10, PLAGL1, KCNQ1OT1, PEG3, GRB10 и PEG1/MEST) в расширенных выборках эмбрионов подтвердило результаты микрочипового анализа как в отношении частот эпимутаций, так и в отношении преобладания соматического гипометилирования аллелей материнского происхождения. Установлено, что потери беременности сопровождаются мультилокусными дефектами метилирования импринтированных генов, частота которых также статистически значимо повышена в плацентарных тканях спонтанных абортусов от женщин с привычным невынашиванием.

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Bocharova A.V., Stepanov V.A., Marusin A.V., Kharkov V.N., Vagaitseva K.V., Fedorenko O.Yu., Bokhan N.A., Semke A.V., Ivanova S.A.
Russian Journal of Genetics. 2017. 53(1), 139–146.
DOI: 10.1134/S1022795417010033

A replicative analysis of associations of 15 SNPs located in the regions of 11 genes (TCF4, VRK2, NOTCH4, ZNF804A, AGBL1, RELN, ZFP64P1, KCNB2, CSMD1, CPVL, NRIP1) and three intergenic regions (SLCO6A1/LINCOO491, LOC105376248/LOC105376249, SPA17/NRGN) with schizophrenia was conducted in the Russian population of the Siberian region. These SNPs were previously identified in genome-wide association studies (GWAS) of schizophrenia and cognitive abnormalities. The present study confirmed associations of KCNB2 rs2247572, CSMD1 rs2616984, and intergenic rs12807809 located in SPA17/NRGN with schizophrenia. It was established that the frequency of the CSMD1 rs2616984 G/G genotype was higher in patients compared to the control group (OR = 1.73; CI: 1.14–2.62; р = 0.0337). The frequencies of the KCNB2 rs2247572 TT genotype (OR = 0.41; CI: 0.20–0.87; р = 0.0485) and intergenic rs12807809 CT genotype located in SPA17/NRGN (OR = 0.70; CI: 0.53–0.94; р = 0.0464) were significantly decreased in patients compared to the control group.

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А.В. Бочарова, В.А. Степанов, А.В. Марусин, В.Н. Харьков, К.В. Вагайцева, О.Ю. Федоренко, Н.А. Бохан, А.В. Семке, С.А. Иванова.
Генетика. 2017. Т. 53. № 1. С. 100-108
DOI: 10.7868/S0016675817010039

Проведено исследование ассоциаций полиморфных локусов, расположенных в генах (TCF4, VRK2, NOTCH4, ZNF804A, AGBL1, RELN, ZFP64P1, KCNB2, CSMD1, CPVL, NRIP1) и межгенных участках (SLCO6A1/LINCOO491, LOC105376248/LOC105376249, SPA17/NRGN) с предрасположенностью к шизофрении в русской популяции Сибирского региона. По данным полногеномных ассоциативных исследований (GWAS) эти маркеры показали ассоциации с риском развития шизофрении и нарушениями когнитивных способностей. В результате нашей работы были подтверждены ассоциации полиморфных вариантов rs2247572 гена KCNB2 и rs2616984 гена CSMD1, а также rs12807809 межгенного участка SPA17/NRGN с риском развития шизофрении. Выявлено, что генотип GG по полиморфному варианту rs2616984 гена CSMD1 статистически значимо чаще встречается у больных, чем в контроле (OR = 1.73; CI: 1.14-2.62; р = 0.0337). Установлено, что частота генотипа ТТ полиморфного маркера rs2247572 гена KCNB2 была статистически значимо ниже у больных, чем в группе контроля (OR = 0.41; CI: 0.20-0.87; р = 0.0485), то же самое было отмечено для частоты генотипа CT полиморфного локуса rs12807809 межгенного участка SPA17/NRGN (OR = 0.70; CI: 0.53- 0.94; р = 0.0464).

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Fedorenko O.Y., Loonen A.J.M., Vyalova N.M., Boiko A.S., Pozhidaev I.V., Osmanova D.Z., Rakhmazova L.D., Bokhan N.A., Ivanov M.V., Freidin M.B. и др.
Physiology and Pharmacology. 2017. 21(1), 25-33
DOI: 10.1111/bcpt.13323

Aripiprazole treatment in schizophrenic patients was previously associated with lower or normalized prolactin levels. Genetic variants in cytochrome P450 (CYP) (CYP2D6), dopamine receptor (DRD2, DRD3) and serotonin receptor (HTR2A, HTR2C) genes were previously associated with antipsychotic-induced hyperprolactinaemia. Our aim was to evaluate whether aripiprazole affects prolactin secretion and its relationship with pharmacogenetics. Thirty-one healthy volunteers receiving a 10-mg single oral dose of aripiprazole were genotyped for 12 polymorphisms in CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by qPCR. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by HPLC-MS/MS. Prolactin concentrations of the 31 volunteers taking aripiprazole and 12 volunteers receiving ibuprofen were determined by ELISA. Prolactin concentrations after ibuprofen intake were considered as control, since it is known to cause no effect. Prolactin concentrations were slightly higher in the aripiprazole group compared to the ibuprofen group. All prolactin pharmacokinetic parameters were higher in females than in males. CYP2D6 poor and intermediate metabolizers had notably higher prolactin Cmax and AUC0-12 than normal and ultrarapid metabolizers. The DRD3 rs6280 polymorphism affected prolactin levels: volunteers carrying Ser/Ser genotype had significantly lower prolactin levels than volunteers carrying the Gly allele. Furthermore, HTR2C rs3813929 C/C homozygotes had significantly lower prolactin levels than T allele carriers. Nevertheless, aripiprazole did increase prolactin levels compared to ibuprofen.

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Triska P., Chekanov, N., Stepanov V., Khusnutdinova E.K., Kumar G.P.A., Akhmetova V., Babalyan K., Boulygina E., Kharkov V., Gubina M., Khidiyatova I., Khitrinskaya I., Khrameeva E.E., Khusainova R., Konovalova N., Litvinov S., Marusin A., Mazur A.M., Puzyrev V., Ivanoshchuk D., Spiridonova M., Teslyuk A., Tsygankova S., Triska M., Trofimova N., Vajda E., Balanovsky O., Baranova A., Skryabin K., Tatarinova T.V., Prokhortchouk E.
BMC Genetics. 2017. 18(Suppl 1), 110.
DOI: 10.1186/s12863-017-0578-3

Background: The history of human populations occupying the plains and mountain ridges separating Europe from Asia has been eventful, as these natural obstacles were crossed westward by multiple waves of Turkic and Uralic-speaking migrants as well as eastward by Europeans. Unfortunately, the material records of history of this region are not dense enough to reconstruct details of population history. These considerations stimulate growing interest to obtain a genetic picture of the demographic history of migrations and admixture in Northern Eurasia.

Results: We genotyped and analyzed 1076 individuals from 30 populations with geographical coverage spanning from Baltic Sea to Baikal Lake. Our dense sampling allowed us to describe in detail the population structure, provide insight into genomic history of numerous European and Asian populations, and significantly increase quantity of genetic data available for modern populations in region of North Eurasia. Our study doubles the amount of genome-wide profiles available for this region. We detected unusually high amount of shared identical-by-descent (IBD) genomic segments between several Siberian populations, such as Khanty and Ket, providing evidence of genetic relatedness across vast geographic distances and between speakers of different language families. Additionally, we observed excessive IBD sharing between Khanty and Bashkir, a group of Turkic speakers from Southern Urals region. While adding some weight to the ""Finno-Ugric"" origin of Bashkir, our studies highlighted that the Bashkir genepool lacks the main ""core"", being a multi-layered amalgamation of Turkic, Ugric, Finnish and Indo-European contributions, which points at intricacy of genetic interface between Turkic and Uralic populations. Comparison of the genetic structure of Siberian ethnicities and the geography of the region they inhabit point at existence of the ""Great Siberian Vortex"" directing genetic exchanges in populations across the Siberian part of Asia. Slavic speakers of Eastern Europe are, in general, very similar in their genetic composition. Ukrainians, Belarusians and Russians have almost identical proportions of Caucasus and Northern European components and have virtually no Asian influence. We capitalized on wide geographic span of our sampling to address intriguing question about the place of origin of Russian Starovers, an enigmatic Eastern Orthodox Old Believers religious group relocated to Siberia in seventeenth century. A comparative reAdmix analysis, complemented by IBD sharing, placed their roots in the region of the Northern European Plain, occupied by North Russians and Finno-Ugric Komi and Karelian people. Russians from Novosibirsk and Russian Starover exhibit ancestral proportions close to that of European Eastern Slavs, however, they also include between five to 10 % of Central Siberian ancestry, not present at this level in their European counterparts.

Conclusions: Our project has patched the hole in the genetic map of Eurasia: we demonstrated complexity of genetic structure of Northern Eurasians, existence of East-West and North-South genetic gradients, and assessed different inputs of ancient populations into modern populations.

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Stepanov V., Marusin A., Vagaitseva K., Bocharova A., Makeeva O.
Genetics Research International. 2017, 6293826
DOI: 10.1155/2017/6293826

Recently, genetic markers rs10503253 and rs2616984 in the CUB and Sushi multiple domains-1 (CSMD1) gene have been reported to be associated with schizophrenia and cognitive functions in genome-wide association studies. We examined the associations of the above SNPs with cognitive performance evaluated by the Montreal Cognitive Assessment (MoCA) tool in a cohort of the normal elderly from the Russian population. Significant association of rs2616984 genotypes with the MoCA scores was found using nonparametric analysis. No association of rs10503253 with MoCA scores was observed using both parametric and nonparametric statistics. Significant combined effect of two-locus CSMD1 genotypes on MoCA scores was demonstrated by median test. Allele ""A"" and genotype ""AA"" of rs2616984 were significantly associated with the lower MoCA scores in comparison of 1st and 4th quartiles of MoCA total score distribution. The results suggest that genetic variants in CSMD1 gene are likely a part of genetic component of cognitive performance in the elderly.

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