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Currently, the question of epigenetic mechanisms of gene regulation in the context of cardiovascular diseases is of considerable interest. Here, DNA methylation profiles of vascular tissues of atherosclerotic patients have been analyzed for the first time using the Infinium Human Methylation27 BeadChip microarray (Illumina, United States). As the result, within 286 genes, 314 CpG sites that varied significantly in the level of DNA methylation between the tissue samples of carotid (in the area of atherosclerotic plaques and nearby macroscopically intact tissues of the vascular wall) and mammary arteries, as well as saphenous veins have been identified. The most pronounced differences in the methylation level was registered for CpG sites of homeobox genes HOXA2 and HOXD4, as well as the imprinted MEST gene. In particular, these genes were found to be hypomethylated in the carotid atherosclerotic plaques compared to their methylation patterns in intact tissues of internal mammary arteries and saphenous veins.

The calcineurin signaling pathway plays a crucial role in the heart remodeling of a different nature, in the development of left ventricular dilatation, and in the progression of heart failure. Components of the calcineurin pathway are involved in the regulation of cardiomyocyte hypertrophy, angiogenesis, and apoptosis. In this study, quantitative expression profiles were determined for major calcineurin pathway genes PPP3CA, PPP3R1, PPP3CB, GATA4, and NFATC4 in the myocardium of the right atrium auricle in patients with ischemic heart disease who underwent different types of surgery depending on the severity of clinical symptoms as follows: surgical reconstruction of left ventricle (LV) geometry (post-infarction aneurysm) or coronary artery bypass grafting (unaltered LV morphology). In patients with sizable post-infarction LV dilatation (n = 21), the expression levels of calcineurin catalytic subunit genes PPP3CA and PPP3CB were 1.3 and 1.6 times lower (p = 0.018 and 0.023, respectively) than in patients with unaltered heart shape (n = 34). The differences in expression levels of PPP3R1, which encodes calcineurin regulatory subunit B and levels of GATA4 and NFATC4, which encode transcription factors, were not significant. Thus, decreased PPP3CA and PPP3CB expression in the atrial myocardium may be a marker of significant post-infarction LV remodeling. The further investigation of the relationship between expression levels of calcineurin pathway genes and the degree of myocardial damage may provide useful insights for predicting adverse events in cardiosurgical treatment of patients with post-infarction heart remodeling.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWA data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms (SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P > 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

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.

For identification of somatic mitochondrial DNA (mtDNA) mutations, the mtDNA major noncoding region (D-loop) sequence in blood samples and carotid atherosclerosis plaques from patients with atherosclerosis was analyzed. Five point heteroplasmic positions were observed in 4 of 23 individuals (17%). Only in two cases could heteroplasmy have resulted from somatic mutation, whereas three heteroplasmic positions were found in both vascular tissue and blood. In addition, length heteroplasmy in a polycytosine stretches was registered at nucleotide positions 303-315 in 16 individuals, and also in the 16184-16193 region--in four patients. The results suggest that somatic mtDNA mutations can occur during atherosclerosis, but some heteroplasmic mutations may appear in all tissues, possibly being inherited.

Analysis of the genome-specific linkage disequilibrium patterns in certain populations is a highly promising approach to the identification of functional variants that underlie susceptibility to complex diseases. In the present study, the linkage disequilibrium patterns of the methylenetetrahydrofolate reductase gene (MTHFR) were examined in a group of patients with coronary atherosclerosis (coronary artery disease, CAD) and in a control sample from the Russian population. It was demonstrated that in the samples from one population, which were differentiated by the presence or absence of CAD, the MTHFR linkage disequilibrium patterns had similar features. Association of the MTHFR rs7533315 and rs2066462 polymorphisms with CAD was demonstrated. In addition, the evolution of the haplotypes and their role in the formation of CAD in the Russian population was reconstructed. The data on the association between genetic variability in the MTHFR locus and pathogenetically important indices of lipid metabolism were obtained. The high informativeness of the haplotype approach in case-control tests for associations with CAD was demonstrated.

In this study, we genotyped polymorphism in GPX1 Pro198→Leu (C→T) rs 1050450 in four groups, i.e., patients with coronary artery disease, people who lived a long time (over 90 years), people who died early (before 55 years) from cardiovascular disease, and the Russian population as a control group. We have found a significant higher T-allele frequency in men with coronary artery disease, i.e., 34.84% (χ2 = 5.228, p = 0.022; OR =1.46), and in men who died early from cardiovascular diseases, 38.16% (χ2 = 6.461, p = 0.011; OR = 1.69) compared to men in the control group, 26.8%. Moreover, a significantly higher genotype TT frequency has been shown in patients with coronary artery disease and myocardial infarction before age 50, which is 19.44% compared to the control group, which was 7.28% (χ2 = 9.55, p = 0.002). The TT frequency in individuals who lived a long time (4.39%) was the lowest and differed significantly from the group with coronary artery disease, which was 12.79% (χ2 = 8.07, p = 0.0045), and from the subgroup with coronary artery disease with myocardial infarction before age 50, which was 19.44% (χ2 = 14.49, p = 0.0001). Thus, our results indicate that the TT allele (Leu) of GPX1 Pro198→Leu (C > T) polymorphism is unfavorable for successful aging; it leads to predisposition to coronary artery disease, early myocardial infarction (before age 50), and early death (before age 55).

This article is a review of scientific publications, in which issues of pathogenetics of multifactorial diseases (MFDs) are considered from the viewpoint of evolution and ontogeny. Concepts explaining significance of evolutionary processes in the formation of genetic architecture of human chronic diseases (“thrifty” genomes and phenotypes, “drifty genes,” decanalization) are analyzed. The roles of natural selection and genetic drift in the formation of hereditary diversity of genes for susceptibility to MFDs are considered. The modern concept of “disease ontogeny” (somatic mosaicism, loss of heterozygosity, paradominant inheritance, epigenetic variability) is discussed. It is demonstrated that the evolutionary and ontogenetic approaches to analysis of genimuc and other “-omic” data are essential for understanding the biology of diseases.

Mutation theory of atherogenesis proved by “loss of heterozygosity” and microsatellite instability in the area of atherosclerotic plaques is complemented by data on epigenetic variability of genetic loci involved in the pathologic process. However, only recently large-scale analysis of epigenetic modifications in the human genome became possible. For the first time, the quantitative microarray-based methylation profiling of 1505 CpG-sites in 807 genes was performed in atherosclerotic plaques of aorta and carotid artery from humans using the GoldenGate Methylation Cancer Panel I (Illumina, United States). One hundred and three (7%) CpG-sites in 90 (11%) genes were differentially methylated between tissue samples. The most pronounced differences in DNA methylation levels were registered for a site located in CpG-island of the imprinted gene H19. By comparing 90 genes that were differentially methylated between tissue samples in our study, 10 genes (ICAM1, GSTM1, IGFBP1, POMC, APOA1, IL1RN, INS, LTA, MMP3, THBS2) were overlapped with data in the Human Genome Epidemiology Network (HuGENet), in which they were identified as candidates for cardiovascular disease continuum.

Genome-wide association studies are currently considered as one of the most powerful tools for establishing the genetic basis of complex diseases. A number of such studies have been carried out for allergic diseases; however, in the Russian population, this analysis has not been performed so far. For the first time, we performed a genome-wide association study of allergic diseases in Russian residents of West Siberia. Two new loci associated with childhood bronchial asthma (20q13.12, rs2425656, P = 1.99 × 10−7; 1q32.1, rs3817222, rs12734001, P = 2.18 × 10−7 and 2.79 × 10−7, respectively) as well as one locus associated with allergic rhinitis (2q36.1, rs1597167, P = 3.69 × 10−7) were identified. Genes located in these loci, YWHAB and PPP1R12B for asthma and KCNE4 for allergic rhinitis, are suggested as new candidate genes for these diseases. It was also found that BAT1 (6p21.33), MAGI2 (7q21.11), and ACPL2 (3q23) are probably common (syntropic) genes of allergic disease and atopic sensitization. It was shown that RIT2 (18q12.3) and FSTL4 (5q31.1) genes can be involved in the control of lung function. The results of the study contribute to the body of data on genetic factors of allergy and expand the list of genes underlying these diseases.

Mutations in three genes PSEN1, PSEN2, and APP are known to be a cause of familial forms of Alzheimer's disease (AD). APOE gene polymorphism is a strong risk genetic factor for AD. We have evaluated allele and genotype frequency distribution of rs11136000 polymorphism in the clusterin (CLU) gene (or apo� lipoprotein J, APOJ) in the samples from three Russian populations and in AD patients. Genomewide asso� ciation studies in samples from several European populations have recently revealed the highly significant association of CLU gene with AD (p = 8.5 × 10 -10 ). We found no differences in allele and genotype frequencies of rs11136000 between the populations from the Moscow, Ural, and Siberia regions. The allele frequencies are close to those in European populations. The genetic association analysis in cohort of AD patients and nor� mal individuals (>500 individuals in each group) revealed no significant association of the rs11136000 poly� morphism in CLU gene with Alzheimer's disease in Russian populations. Although our results showed that the CLU gene polymorphism rs11136000 is likely not a major genetic factor for the common form of Alzhe� imer's disease, the data do not rule out the possibility of a modest effect of CLU and interaction between CLU and APOE genotypes in etiology of Alzheimer's disease.

We tested the association of deletion polymorphism in the GSTT1 and GSTM1 genes for glutathione S-transferases and the A313G single-nucleotide polymorphism in the GSTP1 gene with cirrhosis morbidity and 4-year survival rate among residents of the Tomsk region, West Siberia. The homozygous deletion of the GSTM1 gene (null genotype) proved to be a protective factor against alcoholic and mixed (viral and alcoholic) liver cirrhosis. The frequency of this genotype in patients of the combined group having cirrhosis of any etiology was 39.2%, in patients with alcoholic cirrhosis it was 39.0%, and in patients with mixed cirrhosis it was 34.2%. This genotype was much more frequent among patients of the control group: 64.6%. The GSTM1 null genotype and the GSTP1 A313G polymorphic variant correlated with survival rate. The survivors had a higher GSTM1 null genotype frequency than the dead patients, 46.6 and 30.2%, respectively; a higher frequency of the GSTP1 AA genotype, 63.1 and 40.5%; and a lower frequency of the GSTP1 AG (A313G) genotype (31.1 and 51.2%). The survival rate in patients with the GSTP1 AA genotype was 2.5 times as high as in GG or AG genotype carriers. In patients with the GSTM1 null genotype, the survival rate was twice as high as in patients without the deletion. The 4-year fatal case probability in patients having the heterozygous GSTP1 AG genotype was 2.3 times higher than in patients with the homozygous AA or GG genotypes.

Many new genetic tests for common multifactorial disorders are becoming available to individuals, including direct-to-consumer genotyping services. Typically, studies of public attitudes reveal a high level of interest for individual genotyping. In a Russian urban population, 85% of 2000 respondents answered positively to a question about their own willingness to undergo predictive genetic testing for preventable health conditions. Gender, age and health status significantly influenced response. Multivariate discriminant analyses revealed that wanting to know about probable future diseases, readiness to improve lifestyles and an interest in learning about individual genome characteristics are the most important predictors for wanting to be tested. Along with the high level of interest, highly overestimated expectations were encountered in many studies. With the low predictive abilities of currently available genetic tests for common disorders, proper interpretation of the data and genetic counseling are essential. There is a need for prospective validation of genetic panels for risk assessments, and for efforts to measure the effects of genetic information disclosure and how this information might contribute to lifestyle changes.

Common (syntropic) genes of allergic diseases (ADs) HLA-DQB1, HLA-DRB1, IL4, IL4RA, MS4A2, HLA-DQA1, LTC4S, IL13, IL10, and TGFB1 have been identified on the basis of information from the HuGENet internet database. The functional realm of these genes is associated mainly with the initiation and regulation of an immune response and inflammation. Importance of these processes in the development of ADs is underlined. The results of cluster analysis of allergic diseases obtained using the data on common genes predisposing to their development are presented. Genetic clusterization of ADs confirms their accepted clinical classification.

Polymorphic markers were studied in mitochondrial DNA and the nuclear POLG1 gene, coding for mitochondrial DNA polymerase γ. Their frequencies were compared between healthy individuals and patients with arterial hypertension, as well as between patients with and without left ventricular hypertrophy. The healthy group was found not to be clearly dominated by the C allele of MspI polymorphism in POLG1. Mitochondrial haplogroup H was more frequent (OR = 0.42; 95%CI 0.17–0.98; p = 0.043) in patients without left ventricular hypertrophy than in patients having this complication. Haplogroup T was more often detected in patients with left ventricular hypertrophy (OR = 6.16; 95%CI 1.17–9.74; p = 0.018). This result suggests the implication of mitochondrial DNA in hereditary susceptibility to cardiovascular diseases.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

In clinical medicine, the phenomenon of polypathy, as a particular object of investigation, was first put forth by French clinicians at the end of the 19 th century through the "arthritismus" doctrine. In the first half of the 20 th century, German paediatricians singled out "syntropias," which are combinations of diseases with common pathophysiological mechanisms, and "dystropias," which are diseases that rarely co-occur in one individual. In the present paper, syntropy/dystropy is defined as a natural generic nonrandom phenomenon with an evolutionary-genetic basis. t he genes involved in the development of syntropy are called "syntropic genes," whereas the genes that co-participate in pathophysiological mechanisms and prevent the co-occurrence of particular phenotypes are called "dystropic genes." Prospects for studying the genetic basis of this phenomenon are highlighted. the publicly available database HuGenet can be used in order to identify syntropic genes, as will be shown as examples in an analysis of c ardiovascular diseases.

We propose a novel universal methodology, Short Oligonucleotide Tandem Ligation Assay (SOTLA), for SNP genotyping. SOTLA is based on using a tandem of short oligonucleotide (TSO) probes consisting of three fragments: the core oligonucleotide and two flanking oligomers, one of which is immobilized onto a solid support and another one contains the biotin label. TSO is self-associated on a complementary DNA template, forms the complex containing two nicks, which are efficiently ligated with DNA ligase giving biotinylated oligonucleotide covalently bound to polymer beads. No ligation of TSO on an imperfect DNA template bearing the base substitution in the core binding site is occurred. We used SOTLA for the highly selective SNP analysis in different DNA fragments of human Y chromosome. Comparison of SOTLA results with those of PCR-RFLP and allele-specific PCR techniques demonstrates that SOTLA ensures the univocal reliable SNP analysis in different PCR fragments varying in length and base composition. The fundamental difference between SOTLA and well known OLA approaches while using T4 DNA ligase is that the accuracy of SNP analysis in OLA is ensured only by the specificity of ligase while that in SOTLA is provided by the specificity of both ligation and hybridization of TSO probes.

The gene pool structure of Teleuts was examined and Y-chromosomal haplogroups composition and frequencies were determined. In the gene pool of Teleuts, five haplogroups, C3×M77, N3a, R1b*, R1b3, and R1a1, were identified. Evaluation of the genetic differentiation of the samples examined using analysis of molecular variance (AMOVA) with two marker systems (frequencies of haplogroups and Y-chromosomal microsatellite haplotypes) showed that Bachat Teleuts were equally distant from Southern and Northern Altaians. In Siberian populations, the frequencies and molecular phylogeny of the YSTR haplotypes within Y-chromosomal haplogroup R1a1 were examined. It was demonstrated that Teleuts and Southern Altaians had very close and overlapping profiles of R1a1 haplotypes. Population cluster analysis of the R1a1 YSTR haplotypes showed that Teleuts and Southern Altaians were closer to one another than to all remaining Siberian ethnic groups. Phylogenetic analysis of N3a haplotypes suggested specificity of Teleut haplotypes and their closeness to those of Tomsk Tatars. Teleuts were characterized by extremely high frequency of haplogroup R1b*, distinguished for highly specific profile of YSTR haplotypes and high haplotype diversity. The results of the comparative analysis suggested that the gene pool of Bachat Teleuts was formed on the basis of at least two heterogeneous genetic components, probably associated with ancient Turkic and Samoyedic ethnic components.

In Russian population of Siberia asthma is usually concomitant with high sensitization to indoor allergens (cat, dog and house dust mites), overproduction of total immunoglobulin E (IgE) and airway hyperreactivity. Definition of genes that predispose to development of various sub-components of the asthma phenotype is important for understanding of etiology of this disease. To map genes predisposing to asthma, we tested 21 microsatellite markers from candidate chromosomal regions in 136 Russian nuclear families with asthma from Siberia. We performed non-parametric analysis for linkage with asthma, total IgE, specific IgE to cat, dog, and dust mites, and spirometric indices (FEV1 (%) – percentage of predicted forced expiratory volume in 1 s, FVC (%) – percentage of predicted forced vital capacity, and FEV1/FVC (%) – Tiffenau index). The most significant linkage was to the candidate region on chromosome 12. Locus controlling cat-specific IgE, which is the most abundant in asthma patients from Siberian population, mapped within the interval between 136 and 140 cM on chromosome 12q24.3, with the suggestive linkage at the marker D12S1611 (LOD = 2.23, P = 0.0007). Total IgE was also linked to this region (D12S1611 – LOD = 1.12, P = 0.012). FEV1 (%) exceeded LOD > 1 threshold for significance with the same locus 12q24.3, but with the peak at a more proximal region at 111.87 cM (D12S338 – LOD = 1.21, P = 0.009). Some evidence of linkage (LOD > 1.0) was also detected for asthma at 6p21.31 (D6S291) and total IgE at 13q14.2 (D13S165). These data indicate that the locus 12q24.3 is the most promising candidate for identification of asthma genes in Russian population of Siberia.

Several forms of pathologies, referred to as Yakut hereditary diseases, have been distinguished on the basis of the results of genetic epidemiological studies of Mendelian diseases in the population of the Republic of Sakha (Yakutia): spinocerebellar ataxia type I, myotonic dystrophy, oculopharyngeal muscular dystrophy, hereditary enzymopenic methemoglobinemia, and 3-M syndrome. These diseases are characterized by a high prevalence among Yakuts as compared to their global incidence in the. Data on the molecular nature of mutations in genes responsible for these hereditary diseases are presented.

Aims: To study the frequency distribution of cytochrome P450 (CYP) functional genetic variants in five Eurasian populations from the territory of Siberia in Russia. Materials & Methods: Unrelated healthy Tuvinians, Buryats, Altaians, Yakuts and Russians (n = 87–88) were genotyped for CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3 and CYP3A5*6. Standard pairwise genetic distances, locus-specific and global Fst statistics were calculated. Results: CYP allele and genotype frequencies demonstrated significant variability. Overall, the degree of between-population variance displayed by CYP SNPs was lower than that recorded from neutral short tandem repeats and Aluinsertion polymorphism, indicating evolutionary conservation of CYP polymorphisms. CYP-based genetic distances were well correlated with the geographic distances across populations (r = 0.822, p = 0.008). Conclusions: Although the tested variants were present in the neighboring, yet secluded, populations at the expected range of frequencies, the observed frequencies were significantly variable across Eurasian populations, indicating potential relevance to clinical decision making. The appropriate class, dose and treatment regimen that lead to optimal therapeutic safety and efficacy are presumed to be governed, at least partially, by genetic determinants. Thus, it is expected that, in the future, genetic markers will serve as diagnostics, informing and guiding clinical decision making. Based on this principle, pharmacogenetic research is aimed at identifying individuals who are expected to benefit from a certain pharmacotherapy, while dramatically reducing the suffering and costs associated with adverse drug reactions (ADRs). Indeed, it has been stated that most of the commonly used drugs are effective in only 25–60% of patients, and more than 2 million cases of ADRs occur

The IL4 C(-590)T, IL4RA Ile50Val, and TNF G(-308)A polymorphisms were tested for association with the chronic development of virus hepatitis, the extent of which was inferred from the liver fibrosis stage. The frequency of allele A of the TNF G(-208)A polymorphism in patients with mild fibrosis was higher (24.5%) than in patients with moderate or severe fibrosis (13.4%) or cirrhosis (8.7%). The frequency of het- erozygous genotype CT of the IL4 C(-590)T polymorphism significantly differed between cirrhosis (68.2%) and moderate or severe fibrosis (39.1%). DOI: 10.1134/S0026893308020052

Gene pool structure of Sakha Republic (Yakutia) native population has been studied: we defined composition and frequencies of Y-chromosome haplogroups for Yakuts. Six haplogroups: C3 x M77, C3c, N*, N2, N3a and R1a1 have been revealed in Yakut gene pool. A greater part of Y-chromosome in Yakut population belongs to N3a haplogroup (89%). All investigated Yakut population samples have low values of gene diversity, calculated based on haplogroup frequencies. Gene differentiation of the investigated samples estimated using the analysis of molecular variance (AMOVA) by two marker systems (haplogroup frequencies and microsatellite haplotypes of Y-chromosome) revealed a portion of interpopulation differences amounting to 0.24 and 2.85%, respectively. Frequencies and molecular phylogeny of YSTR-haplotypes were revealed for N3a haplogroup of Y-chromosome. Altogether forty haplotypes were found in Yakuts. Evenks and Yakuts are characterized by overlapping and very specific spectrum of N3a haplotypes, which is not typical for other Siberian ethnic groups. Cluster analysis of populations by N3a YSTR-haplotypes shows Yakut isolation from Turkic-speaking populations in the South Siberia. Genetic diversity generation time for a specific spectrum of Yakut haplotypes was estimated as 4.45 +/- 1.96 thousand years. As opposed to the data on mtDNA, the obtained results give an evidence for significant contribution of a local palaeolithic component into Y-chromosomal Yakut gene pool. Ethnogenetic reconstruction of the present picture of genetic diversity in N3a haplogroup in the territory of Siberia is under consideration.

The IL4 C(−590)T, IL4RA Ile50Val, and TNF G(−308)A polymorphisms were tested for association with quantitative traits important for chronic virus hepatitis, including the levels of IL4, IL10, IL12, TNF-α, fibronectin, collagenase, the proteinase inhibitor, macroglobulin, and free and protein-bound (PBO) oxyproline. Allele A of the TNF G(−308)A polymorphism was associated with a lower TNF-α production by mononuclear cells, a higher production of IL4 and IL12, and a lower PBO level. The genotype CT of the IL4 C(−590)T polymorphism was associated with a high PBO level.

Association of different alleles of immune response modifier genes IL1B (+3953A1/A2), IL1RN (VNTR), IL4 (3′-UTR G/C), IL4RA (I50V), IL12B (1188A/C), and VDR (F/f and B/b) with celiac disease (CD) and its clinical forms was investigated in a family cohort of CD patients from the Tomsk region (N = 139, including 49 probands, i.e., affected children). The control group comprised 129 healthy Russians from Tomsk. A case-control study did not associate any of the polymorphic markers with CD. In a family-based study, the 3′-UTR G/C polymorphism of IL4 was associated with CD (P = 0.024), its atypical form (P = 0.001), and its complications such as osteopenia (P = 0.039) and autoimmune thyroiditis (P = 0.042). IL4RA and VDR polymorphisms I50V and F/f were associated with the typical form of CD (P = 0.001 and P = 0.009, respectively). In general, associations with CD phenotypes were shown primarily for polymorphisms of the genes involved in Th2 immunity.

To date, a wide range of assisted reproductive technologies is available for patients with impaired fertility. In general, the current methods of reproductive medicine are considered safe and do not significantly increase the frequency of birth of children with diseases or congenital malformations. However, the evidence has been accumulating in literature on higher risk of genomic imprinting diseases (Beckwith-Wiedemann and Angelman syndromes) as a result of using assisted reproductive technologies. In most cases examined, the appearance of these syndromes was explained by defective methylation status of imprinted genes. It has been suggested that manipulations with gametes and embryos during the period of total epigenetic modification of their genomes may act as potential risk factors of assisted reproductive technologies. Moreover, overcoming many natural reproductive barriers may contribute to the development of some pathological phenotypes. The review summarizes current views on epigenetic risk factors associated with assisted reproductive technologies.

Цель. Изучение полиморфных маркеров генов нейрональной и эндотелиальной синтаз оксида азота (NOS1 и NOS3), а также иммунологических показателей (клеточный иммунитет, гуморальный иммунитет, структурно-метаболический статус и функциональная активность нейтрофильных гранулоцитов) у больных СД1 на популяционном и семейном уровне. Материалы и методы. Для исследования было выбрано два дизайна. Первый дизайн: случай (163 ребенка больных СД1) ? контроль (243 индивида русской национальности, проживающих в Томске и не имеющих по данным клинического, инструментального обследования СД1 и признаков сердечно-сосудистых нарушений). Второй дизайн: случай (80 детей и подростков больных СД1) ? контроль (родственники первой степени родства ? 220 человек). Были изучены один полиморфный маркер гена NOS1 ? C/T (в 18 экзоне) и четыре полиморфных маркера гена NOS3 (VNTR в интроне 4, -691C/T в области промотора и две нуклеотидные замены ? 774С/T, 894G/T в 6-м и 7-м экзонах соответственно). Результаты. Анализ методом ?случай-контроль? (больные сахарным диабетом ? здоровые лица) показал наличие статистически значимой ассоциации полиморфного маркера С/Т гена NOS1, при этом OR составил 1,491. Дети с генотипом ВВ полиморфного маркера VNTR гена NOS3 имели достоверно меньшее отношение CD4/CD8, чем дети с генотипами АА и АВ, что обусловлено снижением количества CD4 у детей с генотипом ВВ. Соотношение CD4/CD8 у больных СД1 с генотипами АА и АВ не отличалось от показателей здоровых детей (2,26?0,19) Томска. Выводы. Больные сахарным диабетом 1 типа русского населения Томской области достоверно чаще являются носителями аллеля С полиморфного маркера С/Т гена нейрональной синтазы NO, аллеля В полиморфного маркера VNTR, аллеля С полиморфного маркера С691Т, аллеля С полиморфного маркера С774Т и аллеля G полиморфного маркера G894Т гена эндотелиальной синтазы NO. Получены следующие ассоциации иммунологических показателей с полиморфными маркерами: CD4/CD8 ? VNTR, поглотительная способность нейтрофилов ? C774T, поглотительная способность нейтрофилов ? G894T гена эндотелиальной синтазы NO.

Y-chromosomal haplogroups composition and frequencies were analyzed in Northern and Southern Altaians. In the gene pool of Altaians a total of 18 Y-chromosomal haplogroups were identified, including C3xM77, C3c, DxM15, E, F*, J2, I1a, I1b, K*, N*, N2, N3a, O3, P*, Q*, R1*, R1a1, and R1b3. The structuring nature of the Altaic gene pool is determined by the presence of the Caucasoid and Mongoloid components, along with the ancient genetic substratum, marked by the corresponding Western and Eastern Eurasian haplogroups. Haplogroup R1a1 prevailed in both ethnic groups, accounting for about 53 and 38% of paternal lineages in Southern and Northern Altaians, respectively. This haplogroup is thought to be associated with the eastward expansion of early Indo-Europeans, and marks Caucasoid element in the gene pools of South Siberian populations. Similarly to haplogroup K*, the second frequent haplogroup Q* represents paleo-Asiatic marker, probably associated with the Ket and Samoyedic contributions to the Altaic gene pool. The presence of lineages N2 and N3a can be explained as the contribution of Finno-Ugric tribes, assimilated by ancient Turks. The presence of haplogroups C3xM77, C3c, N*, and O3 reflects the contribution of Central Asian Mongoloid groups. These haplogroups, probably, mark the latest movements of Mongolian migrants from the territory of contemporary Tuva and Mongolia. The data of factor analysis, variance analysis, cluster analysis, and phylogenetic analysis point to substantial genetic differentiation of Northern and Southern Altaians. The differences between Northern and Southern Altaians in the haplogroup composition, as well as in the internal haplotype structure were demonstrated.

The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymor- phism A/G ( 47His )), ADH7 (intron 5 polymorphism G/C ) and cytochrome P450 2E1 gene ( CYP2E1 ; 5'-flank- ing region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy popula- tion and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Wein- berg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B * G (+ Msl I) allele, CYP2E1 * C2 (+ Pst I) allele and CYP2E1 * C (- Dra I) allele were 8.48 ± 1.86, 1.20 ± 0.69, and 10.00 ± 1.90%, respectively. The ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7*C (- Sty I) allele was 44.58 ± 3.21%. A significantly higher frequency of CYP2E1 Pst I C2 allele has been revealed in the CA group ( P = 0.043; OR = 4.23; 95% CI 1.03-20.01). The tendency to significant effect of A1A2 genotype in ADH1B Msl I polymorphism was observed for systolic blood pressure in the control group ( P = 0.068). The statistically significant two-way interaction effects of ADH7 Sty I and CYP2E1 Dra I on diastolic blood pressure ( P = 0.029) and on the serum high density lipoprotein level ( P = 0.042) were also revealed. Association of A1A2 genotype in ADH1B Msl I polymorphism with reduced amount in a serum of a very low density lipoprotein level ( P = 0.045) have also been shown. This may result from mul- tifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.

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 alien Russian population. 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 Gwas 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the alien Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.1365 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.

Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non–random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the “My Gene” genomic service (www.i–gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype “IHD only,” including those in the APOB, CD226, NKX2–5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the “IHD and AH” phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the “IHD only” and “IHD and AH” phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the “IHD and AH” phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the “syntropy” and “IHD only” phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid–metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the “IHD only” phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated “single” forms of a disease.

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.

A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19-2.45; р = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05-2.40; р = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06-4.17; р = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07-2.50; р = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03-2.12; р = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02-2.11; р = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.

The distribution of the allele and genotype frequency for the TOMM40 gene polymorphic variants rs741780, rs157580, rs1160985, rs2075650, and rs8106922 was analyzed in a sampling of ethnic Russians from the city of Kemerovo. The study of the structure of linkage disequilibrium in terms of five studied polymorphic variants showed the presence ofa haplotype block 2 Kb in length, which includes three polymorphic variants, i.e., rs741780, rs1160985, and rs8106922. The differences in the frequencies of alleles and genotypes in terms of the polymorphic rs2075650 and rs157580 variants between ethnic Russians from the city of Kemerovo and other European populations were detected. It was discovered that polymorphic variants of TOMM40 rs741780, rs1160985, and rs8106922 are associated with serum triglyceride concentrations. In men, the polymorphic variant rs2075650 is associated with low-density lipoprotein cholesterol levels. In women, the polymorphic variant rs741780 is associated with diastolic blood pressure levels.

We have performed association analysis for mtDNA most common variants and haplogroups with myocardial infarction and some prognostic characteristics in patients. Comparison of patients (N=406) and controls (N=183) has shown higher frequency of HV0 haplogroup in patients (6.9% vs. 2.2%; p=0.033). Patients with early infarction (before age 55), comparing to patiens older than 55 and the first infarction, had higher frequency of 16189C variant (24.1 vs. 12.5%; p=0.008); also, haplogroup U2e was registered only in the subgroup with early infarction (4.4%; p=0.004). On the other side, haplogroup U5 was less frequent in the patients with early infarction (5.1% vs. 15.4%; p=0.002). The patients with recurring cardiovascular incidents during one year follow-up had higher frequency of haplogroup H1 (20% versus 4.5% in the patients without complications, p=0.002) and variant 16189C (30% versus 13.5%; p=0.018). Haplogroup U5 was more frequent in the group of patients with left ventricular ejection fraction less than 40%: 17.1% comparing to 8.2% in the group with ejection fraction40%; p=0.034. The results suggest that mtDNA polymorphism contributes to coronary atherosclerosis. The associations could be explained by the polymorphism effect on oxidative phosphorylation and reactive oxygen production in mitochondria.

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.

In most cases, the cause of embryo and fetus death remains unclear although the multifactorial reasons are suspected. The polymorphic C677T and A1298C variants of the MTHFR gene are associated with hyperhomocysteinemia, which is a risk factor of early pregnancy loss. The aim of this study is analysis of genotypes and haplotypes of C677T and A1298C polymorphic variants of MTHFR genes in the groups of spontaneous abortions with normal karyotype and newborns in the Tomsk population. Between these groups, no statistically significant differences were determined in the allele, genotype, and haplotype distributions of C677T and A1298C polymorphisms of the MTHFR gene. The haplotype frequencies of C677T and A1298C polymorphic variants of MTHFR gene in the Russian populations, which proved to be similar to those in most European populations, are presented for the first time.

The results of the first Russian study of polymorphisms of tuberculosis (TB) susceptibility genes SLC11A1, VDR, IL12B, IL1B, IL1RN in Tuvinians from Tuva Republic and Russians from Tomsk city are presented. In Tuvinians, as compared with Russians, the significantly higher prevalence of potentially disease-associated alleles of the genes studied was shown: SLC11A1*543N (0.139 and 0.043, respectively, p = 4.6E-5), IL12B*1188C (0.378 and 0.174, respectively, p = 1.1E-8), VDR*b (0.825 and 0.532, respectively, p = 3.2E-16), IL1B*(+3953A1) (0.865 and 0.806, respectively, p = 0.035). However, no one of these alleles was associated with TB in Tuvinians, whereas, in Russians TB patients, in comparison with the controls, there was a higher prevalence of the following markers: IL1RN*A2 (0.258 and 0.186, respectively, p = 0.024), SLC11A1*274T (0.251 and 0.164, respectively, p = 0.009), IL12B*1188C (0.240 and 0.174, respectively, p = 0.044), ILIB*(+3953A2) (0.259 and 0.194, respectively, p = 0.044). Distinct patterns of linkage disequilibrium between pairs of the polymorphisms studied in Tuvinians and Russians were shown. At whole, the data obtained demonstrate the ethnic specificity of the distribution and pathogenetic significance of the alleles of the TB susceptibility genes.

The allele and genotype frequency distributions of four STRs (the LPL, vWA, FES/FPS, and F13B loci) commonly used in forensic medicine were studied with a sample of 200 ethnic Russians from Siberia. Genetic and molecular diversity of the four STRs was characterized in comparison with the American Caucasoid population. The set of the four STRs showed a high power of discrimination (PD = 0.99975). Comparison of the genetic variation at the four loci revealed a considerable difference between the Russian and American Caucasoid populations, precluding the use of data on allele frequencies in American Caucasoids for forensic testing in Russia. The results can be used as a reference in Siberia.

The Ile50Val polymorphism of the IL4RA gene was tested for association with chronic viral hepatitis and the character of its progression (the stage of hepatic fibrosis). In total, 61 patients were examined. The control group was a random sample of Tomsk residents (N = 128). Genotyping was based on RFLP analysis. The allele and genotype frequencies of the Ile50Val polymorphism did not significantly differ between the patients and the controls. However, a significant difference in genotype frequency distribution was observed for the patients with different stages of hepatic fibrosis. The frequency of heterozygotes Ile/Val in patients without signs of fibrosis was lower than in the control group (7.1% vs. 51.6%, P = 0.002), while the frequency of the homozygous genotypes was higher. In addition, this subgroup significantly differed in genotype frequency distribution from subgroups of patients with early or severe fibrosis (P = 0.035 and P = 0.004, respectively).