The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the arrived Russian population (Tomsk). All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele G was 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the arrived Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.13365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians.

Охарактеризована изменчивость потенциально функционально значимых полиморфных вариантов rs2069705 (5UTR гена IFNG), rs17880053 (вблизи 5UTR гена IFNGR2), rs11126176 (псевдоген LOC100287361) и rs804271 (вблизи 5UTR гена NEIL2) у представителей четырех этнических групп, проживающих в Сибирском регионе: трех коренных монголоидных этносов – якутов (жители Республики Саха (Якутия)), тувинцев (Республика Тува) и бурят (Республика Бурятия), а также пришлого русского населения (г. Томск). Все изученные варианты были полиморфными. Частота аллеля С по rs2069705 у русских составила 0.5833, у представителей коренных народностей находилась в границах 0.7842–0.8967; частота делеции по rs17880053 у русских – 0.8073, у коренных этносов – 0.4474–0.5521; частота аллеля А по rs11126176 была равна 0.5398 у русских и с меньшей величиной регистрировалась у коренных этносов – 0.2722–0.4551; по rs804271 частота аллеля G у русских – 0.5215 и у коренных этносов – 0.2527–0.4022. По генотипической структуре пришлое русское население существенно дистанцировано от монголоидных коренных популяций – генетические дистанции между русскими и якутами – 0.0742, русскими и тувинцами – 0.1365, русскими и бурятами – 0.1433. Среди монголоидных коренных этносов Сибири наиболее удалены друг от друга тувинцы и якуты – 0.0262, генетические дистанции между якутами и бурятами были равны 0.0151, между бурятами и тувинцами – 0.0127.

In this review, the development of ideas focused on the phenomenon of disease combination (comorbidity) in humans is discussed. The genetic bases of the three forms of the phenomenon, comorbidity (syntropias), inverse comorbidity (dystropias), and comorbidity of Mendelian and multifactorial diseases, are analyzed. The results of personal genome-wide association studies of the genetic risk profile that may predispose an individual to cardiovascular disease continuum (CDC), including coronary heart disease, type 2 diabetes, hypertension, and hypercholesterolemia (CDC syntropy), as well as the results of bioinformatic analysis of common genes and the networks of molecular interactions for two (bronchial asthma and pulmonary tuberculosis) diseases rarely found in one patient (dystropy), are presented. The importance of the diseasome and network medicine concepts in the study of comorbidity is emphasized. Promising areas in genomic studies of comorbidities for disease classification and the development of personalized medicine are designated.

В обзоре рассмотрена динамика представлений о феномене сочетания болезней (коморбидности) у человека. Представлен анализ генетических основ трех форм феномена: коморбидность (синтропии), “обратная коморбидность” (дистропии), а также коморбидность менделевских и многофакторных болезней. Приведены результаты собственного геномного ассоциативного исследования генетического профиля предрасположенности к болезням сердечно-сосудистого континуума (ССК) – ишемической болезни сердца, сахарного диабета 2 типа, артериальной гипертонии и гиперхолестеринемии (синтропия ССК), а также биоинформационный анализ общих генов и сетей молекулярных взаимодействий для двух (бронхиальная астма и туберкулез легких) редко встречающихся у одного пациента болезней (дистропия). Подчеркнута важность концепций “дизисома” и “сетевой медицины” в исследовании коморбидности. Обозначены перспективы геномных исследований коморбидности для классификации болезней и развития персонализированной медицины.

The study aimed to reveal cancer related mutations in DNA repair and cell cycle genes associated with chronic occupational exposure to gamma-radiation in personnel of the Siberian Group of Chemical Enterprises (SGCE). Mutations were analyzed by comparing genotypes of malignant tumors and matched normal tissues of 255 cancer patients including 98 exposed to external gamma-radiation (mean dose 128.1±150.5mSv). Also a genetic association analysis was carried out in a sample of 149 cancer patients and 908 healthy controls occupationally exposed to gamma-radiation (153.2±204.6mSv and 150.5±211.2mSv, respectively). Eight SNPs of genes of DNA excision repair were genotyped (rs13181, rs1052133, rs1042522, rs2305427, rs4244285, rs1045642, rs1805419 and rs1801133). The mutation profiles in heterozygous loci for selected SNP were different between sporadic tumors and tumors in patients exposed to radiation. In sporadic tumors, heterozygous genotype Arg/Pro of the rs1042522 SNP mutated into Arg/0 in 15 cases (9.6%) and 0/Pro in 14 cases (8.9%). The genotype Lys/Gln of the rs13181 SNP mutated into Lys/0 and 0/Gln in 9 and 4 cases, respectively. In tumors of patients exposed to low-level radiation, the rs1042522 Arg/0 mutated genotype was found in 12 cases (12.1%), while in 2 cases (2%) 0/Pro mutation was observed. Finally, the rs13181 0/Gln mutated genotype was observed in 15 cases (16,5%) . Thus, our study showed the difference in patterns of allelic imbalance in tumors appeared under low-level radiation exposure and spontaneous tumors for selected SNPs. This suggests different mechanisms of inactivation of heterozygous genotypes in sporadic and radiation-induced tumors.

Epigenetic mechanisms of gene regulation in context of cardiovascular diseases are of considerable interest. So far, our current knowledge of the DNA methylation profiles for atherosclerosis affected and healthy human vascular tissues is still limited. Using the Illumina Infinium Human Methylation27 BeadChip, we performed a genome-wide analysis of DNA methylation in right coronary artery in the area of advanced atherosclerotic plaques, atherosclerotic-resistant internal mammary arteries, and great saphenous veins obtained from same patients with coronary heart disease. The resulting DNA methylation patterns were markedly different between all the vascular tissues. The genes hypomethylated in athero-prone arteries to compare with atherosclerotic-resistant arteries were predominately involved in regulation of inflammation and immune processes, as well as development. The great saphenous veins exhibited an increase of the DNA methylation age in comparison to the internal mammary arteries. Gene ontology analysis for genes harboring hypermethylated CpG-sites in veins revealed the enrichment for biological processes associated with the development. Four CpG-sites located within the MIR10B gene sequence and about 1 kb upstream of the HOXD4 gene were also confirmed as hypomethylated in the independent dataset of the right coronary arteries in the area of advanced atherosclerotic plaques in comparison with the other vascular tissues. The DNA methylation differences observed in vascular tissues of patients with coronary heart disease can provide new insights into the mechanisms underlying the development of pathology and explanation for the difference in graft patency after coronary artery bypass grafting surgery.

Purpose: Double-strand breaks (DSB) repair and apoptosis are assumed to be key factors in the determination of individual variability in response to radiation treatment. In this study we investigated tumor protein p53 (TP53) binding protein 1 (53BP1) and phosphorylated histone 2A family member X (γH2AX) foci, γH2AX pan-staining and late apoptosis/necrosis (LAN) in lymphocytes from breast cancer (BC) patients undergoing radiotherapy.

Materials and methods: BC patients were subjected to local radiotherapy with fractionated doses using linear accelerator. Adverse reactions of patients were classified according to the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) criteria. Blood samples were collected before treatment, at various time-points during and after radiotherapy. Residual 53BP1 and γH2AX foci, γH2AX pan-staining were analyzed in peripheral blood lymphocytes (PBL) using the Metafer system and confocal laser scanning microscopy. LAN cells were counted by the trypan blue (TB) exclusion assay. Statistical analysis was performed using Mann-Whitney test, Spearman rank correlation test and analysis of covariance (ANCOVA).

Results: No statistically significant changes were observed in the levels of γH2AX foci during radiotherapy. In contrast, radiation-induced residual 53BP1 were detected already after the first fraction. Increased individual variability in the 53BP1 focus formation was observed during treatment. The background level of DNA repair foci and its individual variability in response to radiotherapy decreased after the end of radiotherapy indicating successful removal of DNA-damaging effects. A correlation between stage of cancer and 53BP1 focus formation was established which suggests the prognostic value of this test. We show that the fraction of LAN cells negatively correlates with the level of 53BP1 and positively correlates with individual radiosensitivity. Only weak correlation was observed between γH2AX pan-staining and LAN cells. Due to large interindividual variability, both in vivo assays, LAN and focus formation, have shown relatively low predictive power at the individual level.

Conclusions: It is likely that radiosensitive patients have less efficient mechanisms of elimination of apoptotic cells with DNA damage resulting in accumulation of LAN cells and facilitating adverse reactions. Our data suggested that the grade of adverse reaction may positively correlate with LAN cells in PBL before and during radiotherapy.

Predicting tumor radiosensitivity has yet to be routinely integrated into radiotherapy. We analyzed the possibility to assess radiosensitivity of tumor cells based on endogenous and radiation-induced 53BP1 foci which are molecular markers of DNA double strand breaks (DSB). In eleven tumor cell lines of different origin, radiosensitivity was assessed by surviving cell fraction following irradiation with 2 Gy (SF2). 53BP1 foci were measured at 4 and 12 h post-irradiation by confocal laser microscopy and dedicated software. The correlation of 53BP1 foci and their post-irradiation kinetics with SF2 was assessed using Spearman rank test. The SF2 correlated with both excess of radiation-induced 53BP1 foci per cell at 4 h after irradiation and decay in number of 53BP1 foci from 4 to 12 h post-irradiation. The fraction of cells with multiple endogenous 53BP1 foci also correlated with SF2 of tumor cells. We conclude that the radiosensitivity of tumor cells can be predicted by kinetics of formation and decay of 53BP1 foci after irradiation. For the first time we report that the fraction of cells with multiple endogenous 53BP1 foci can be used as a marker of tumor cell radiosensitivity.

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Invasive micropapillary carcinoma (IMPC) is a rare (up to 2%) and aggressive form of breast cancer.1 ,2 IMPC shows high intratumoral morphological diversity, which represents the degree of cell differentiation, as well as the architectural and invasive growth patterns of tumour cells. Morphologically, these tumours are characterised by the presence of hollow-like (tubular) and morula-like (alveolar) structures of cuboidal-to-columnar neoplastic cells, which are surrounded by empty spaces (retraction clefts) and display an inversion of cell polarity, detected by aberrant localisation of glycoprotein MUC-1 at the stromal–basal surface.1 ,3 In addition, micropapillary tumour clusters can be represented by tumour cells arranged in solid patterns (structures), trabecular structures and discrete (small) groups.3–6 It has been suggested that morphological diversity of IMPC is related to chemotherapy resistance,7 whereas the presence of retraction clefts around tumour clusters is associated with increased lymphangiogenesis and lymph node metastasis.8

Considerable intratumour morphological heterogeneity in breast cancer most likely results from genetic and epigenetic instability of the tumour cells.9 ,10 Previously, the relationships between morphologically distinct components and specific chromosome aberrations have been found in metaplastic and invasive ductal breast carcinomas,11 ,12 the latter is now classified as invasive carcinoma of no special type (IC NST), and is the most common histological type of breast cancer.1

IMPC demonstrates a heterogeneous pattern of chromosome aberrations, and tends to be genetically a more complex disease than IC NST.11 ,12 IMPC more often harboured gains of chromosomes 1q, 8q, 17q and 20q, and losses of 1p, 8p, 13q, 16q and 22q,13 ,14 which were emphasised by Marchio and coauthors13 as previously associated with breast tumours of high histological grade. In contrast, concurrent gain of 1q and 16p and deletion of 16q, related to low

Objective: The study was designed to assess the effects of polymorphisms in genes associated with essential hypertension on the variation of erythrocyte membrane proteins (EMPs) in hypertensive patients.

Methods: Major EMPs content was analyzed in blood from 1162 unrelated Russians (235 hypertensive patients, 176 healthy controls, and 751 random individuals from the Central Russia population). Essential hypertension patients were genotyped for 11 polymorphisms of essential hypertension susceptibility genes including ADD1 (rs4961), GNB3 (rs5443, rs16932941), NOS3 (rs1799983, rs2070744), ACE (rs5186), AGTR1 (rs5186), AGT (rs699, rs4762), MR (rs5534), and TGFB1 (rs1800471). EMP contents and their relationship with the genetic loci were analyzed using various statistical tests.

Results: Sex-specific differences in EMP contents between the cases and controls were observed. Regardless of sex, hypertensives exhibited mainly decreased levels of alpha (SPTA1) and beta-spectrin (SPTB) and increased levels of glucose transporter (GLUT1) as compared with healthy subjects (P ≤ 0.001). EMP correlated differently in essential hypertension patients and controls. Almost 70% of the joint variation in the EMP levels is explained by five gender-specific principal components. The essential hypertension susceptibility genes showed considerable effects on the levels of spectrins and glucose transporter. A joint variation of the genes explained about half the total polygenic variance in the GLUT1, SPTA1, and SPTB levels in hypertensives.

Conclusions: The study showed that essential hypertension susceptibility genes are the important factors of the inherited EMP variation, and their pleitropic effects may be mirrored in the altered expression of genes encoding cytoskeletal proteins and those related to intracellular glucose metabolism.

Objectives: Atypical familial mycobacteriosis (AFM, OMIM #209950) is caused by mutations in genes regulating IL12/IFNG pathway. Some of the mutations exhibit incomplete penetrance, and they have been proposed to be involved in the common (polygenic) predisposition to tuberculosis (TB). We set out to test this hypothesis in two populations from Siberian region of Russia with high prevalence of TB.

Material and methods: The prevalence of twelve mutations in IL12/IFNG pathway genes of were analysed in 331 Russians and 238 Tuvinians TB patients and in 279 healthy Russians and 265 healthy Tuvinians. A screening for new mutations and rare polymorphisms was carried out in 10 children with severe generalized TB and severe BCG-vaccine complications using Sanger's bidirectional sequencing.

Results: Twelve mutations most commonly identified in AFM patients appeared to be ""wild-type"" monomorphic in the studied groups. No new mutations or rare polymorphisms were identified by sequencing. However, 15 common single nucleotide polymorphisms were found, none of which was associated with TB after correction for multiple testing.

Conclusion: The results of the study contradict with a hypothesis that mutations underlying AFM syndrome are involved in the predisposition to TB.

В публикации приведены данные официальной статистики о репродуктивном здоровье населения Республики Бурятия и некоторые сведения о факторах, определяющих уровень репродуктивного здоровья населения Республики Бурятия (отдельные аспекты бесплодного брака, осложнения беременности, гендерное поведение, генетические маркеры). Совокупная оценка этих параметров необходима для прогноза здоровья и разработки индивидуальных рекомендаций по профилактике нарушений в репродуктивной сфере с учетом этнической принадлежности.