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Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) of TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) was estimated in the Slavs of West Siberia. We further investigated an association of SNPs in TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461), and ABTB2/ САТ (rs2022318) genes with bronchial asthma (BA), arterial hypertension (AH) and their comorbidity. Then, the disease-associated SNPs were annotated in silico in relation to their potential regulatory functions. Strong LD was detected between rs1928298 and rs1927914, as well as rs7026297 and rs7038716 in the Slavs of West Siberia. It was found that the rs1927914 G allele of the TLR4 gene and the rs1980616 C allele of the SERPINA1 gene are associated with the predisposition to BA. These SNPs can affect binding affinity of transcription factors of the Pou and Klf4 families, as well as the expression levels of the TLR4 and SERPINA1 genes. The rs11065987 allele A of the ATXN2/BRAP genes, the rs11669386 A allele of the CARD8 gene, the rs2284033 allele G of the IL2RB gene, and the rs11191582 allele G of the NT5C2 gene were associated with the risk of AH. These variants can alter binding affinity of the Hoxa9, Irf, RORalpha1 and HMG-IY transcription factors, as well as the expression levels of the ALDH2, CARD8, NT5C2, ARL3, and SFXN2 genes in blood cells/vessels/heart, respectively. The risk of developing a comorbid phenotype of AD and AH is associated with the A allele of rs7038716 and the T allele of rs7025144 of the TLR4/AL160272.2 genes, the A allele of rs1010461 of the ANG gene and the C allele of rs2022318 of the ABTB2/CAT genes. Variants rs7038716 and rs7025144 can change the expression levels of the TLR4 gene in blood cells, while rs1010461 and rs2022318 influence the expression levels of the ANG and RNASE4 genes as well as the CAT and ABTB2 genes in blood cells, lungs/vessels/heart.

The study of the phenomenon of a combination of several diseases at the same time in an individual, actualized in the second half of the 19th century, is being actively analyzed 150 years later using genetic approaches. We present an overview of the results of such studies in relation to allergic diseases, in particular, a special variant, the so-called «atopic march», the sequential development of eczema, allergic rhinitis and asthma («atopic march» syntropy). The data of genetic and epidemiological studies were summarized, the analysis of genome-wide associative studies was carried out, and the role of mutations in the filaggrin gene (FLG) in the development of the «atopic march» syntropy was considered.

Co-occurrence of cardiovascular diseases is significantly common among patients with bronchial asthma. Genetic factors can have a significant effect on the development of hypertension in patients with asthma. Objective of the study was to investigate the associations of polymorphic variants relating to quantitative changes in the expression profile (eQTL) of the CAT, TLR4, and IL10 genes with the development of bronchial asthma co-morbid with arterial hypertension.Material and methods. Genotyping of 48 eQTL SNPs of the CAT, TLR4, and IL10 genes was performed using MALDI-TOF mass spectrometry in patients with «isolated» asthma (n = 145) and arterial hypertension (n = 144) and their combination (n = 146), as well as in the control group of healthy individuals (n = 152). Using logistic regression, an analysis of the associations of haplotypes with the studied diseases was carried out.Results. An association of bronchial asthma in combination with arterial hypertension with haplotypes formed by eQTL SNPs of the CAT and TLR4 genes was established. The spectrum of haplotypes associated with comorbidity of asthma and hypertension differs from the haplotypes associated with “isolated” asthma.Conclusion. The molecular base of asthma and hypertension comorbidity can be associated with variants that control the expression of TLR4 and CAT genes.

Atopic bronchial asthma (ABA) is a multifactorial disease; its development is dependent on many environmental and genetic factors. Genetic risk factors can affect the clinical phenotype of ABA and the level of therapeutic control over the disease. Cytokine genes are crucially important in pathogenesis of ABA as they encode proteins participating in immune response and development of inflammation in bronchi. It was suggested that the therapeutic control of the disease is genetically mediated and depends on the presence of one or another allele in genes of mediators, participating in ABA pathogenesis. The knowledge about genetic markers will allow to predict clinical course of ABA in children. We carried out the analysis of association between genes of pro- and anti-inflammatory cytokines with the level of therapeutic control of ABA. In children with controlled and uncontrolled ABA (CABA and UABA, respectively; n = 110), and in general a population sample (n = 138), we analysed 11 polymorphisms: IL2 (rs2069762), IL4 (rs2070874 и rs2243250), IL5 (rs2069812), IL10 (rs1800872 and rs1800896), IL12B (rs3212227), TNFA (rs1800629 and rs1800630), TGFB1 (rs1800469), and IFNG (rs2069705), encoding cytokines actively participating at the development of allergic inflammation. According to results of present study, the prevalence of alleles and genotypes of the analysed loci in the East Siberia Caucasians is consistent with the data in other world Caucasian populations. We have found statistically significant differences between UABA and control groups for the prevalence of IL2 (rs2069762) polymorphism: GG genotype was more common in control group (14.1% compared to 5.9%, р = 0.03). It was shown that the IL2*T allele and ТТ genotype of the rs2069762 are associated with the increased risk of uncontrolled ABA. A comparison of the haplotypes of IL4 (rs2070874 and rs2243250) gene with correction for sex and age within an additive model revealed that the most common haplotype СC (prevalence in ABA/CABA/UABA groups is 0.75/0.76/0.74, respectively) is protective against the development of ABA (RR 0.53±0.32; p = 0.044). A comparative analysis of TNFA (rs1800629 and rs1800630) haplotypes has shown the GC haplotype to be protective against the risk of ABA (RR 0.59±0.17; р = 0.003) while the GA haplotype is positively associated with the disease (RR 2.07±0.25; р = 0.003). This was true for BA, regardless of the control over the disease (CABA GA: RR 1.93±1.2; p = 0.041; UABA GA: RR 2.43±0.31; p = 0.005). Thus, it was established that the studied cytokine genes are important for the development of ABA in children. These data were obtained for the first time for Caucasians of East Siberia. They are of interest in terms of accumulation of the data about the impact of cytokine genes polymorphism upon development of ABA and its therapeutic control in children.

Tuberculosis (TB) is a common disease caused by infection of Mycobacterium tuberculosis and influenced by host hereditary and environmental factors. Accumulated genomic data obtained through the use of new methodological approaches, including analysis of associative networks, contribute to the understanding of the hereditary basis of the disease. In the current study, we carried out the reconstruction and analysis of associative network representing molecular genetic links between proteins/genes involved in the development of TB. In the associative network, well studied proteins and genes with a decisive importance in the efficiency of the human immune response against a pathogen predominated. However, this approach identified 12 new genes encoding for the respective proteins in the associative network polymorphismsof which has not been studied regarding the development of TB.

This review focuses at the problem of the genetic basis of comorbidity. We discuss the concepts and terms relating to combinations of diseases. The guidelines of the study of comorbidity using modern high throughput methods and approaches of genetics, molecular biology and bioinformatics are designated. In this review we present results of studies showing genetic specificity for the combined phenotypes dif-ferent from the isolated disease, we considergene-gene and gene-environment interactions in comorbidity. We also discuss the role of single nucleotide polymorphisms and structural genome variations in the development of comorbidity. Own results of researching shared genes of inversely comorbid diseases like as bronchial asthma and tuberculosis are presented.

BACKGROUND:Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS:We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS:First approach: 50 SNPs were selected based on an overall interaction effect at p

Introduction: The leading mechanisms and causes of severe therapy resistant asthma are poorly understood. The aim of this study was to define global patterns of gene expression in adults with severe therapy-resistant asthma in dynamic during treatment period.Methods: Performed 24-week prospective interventional study in parallel groups. Severe asthma patients was aposterior divided at therapy sensitive and resistant patients according to ATS criteria. Global transcriptome profile was characterized using the Affymetrix HuGene ST1.0 chip. Cluster analysis was performed.Results and conclusion: According to our data several mechanisms of therapy resistance may be considered: increased levels of nitric oxide and beta2-agonists nitration, dysregulation of endogenous steroids secretion and involvement in the pathogenesis of Staphylococcus aureus. Absence of suppression of gene expression KEGG-pathway “asthma" may reflect the low efficiency or long period of anti-inflammatory therapy effect realization.

Crohn’s disease (CD) and tuberculosis (TB) share several mechanisms of pathogenesis, and this suggests they also have common genetic susceptibility factors. To test this hypothesis, we performed the analysis of association between TB and polymorphisms of genes associated with CD, according to the results of genome-wide association studies, in Russians from Tomsk and indigenous people from Tuva. For the first time, The rs2872507 (ORMDL3), rs3810936 (TNFSF15), rs10192702 (ATG16L1), rs9286879 (1q24.3), rs10507523 (13q14.11) polymorphisms were found to be associated with TB in Russians. The rs1407308 (TNFSF15) and rs1736135 (21q21.1) were associated with the disease in Tuvinians. The associations found are likely due to the functional role of the relevant proteins and their pathogenetic influence on the immune reaction underlying tuberculosis infection. Overall, the study of polymorphisms associated with CD allowed us to identify new candidate genes for TB.

To investigate the molecular mechanisms of human immune response modification by Opisthorchis felineus antigens in bronchial asthma. The experimental study was performed with cell cultures from patients with bronchial asthma, patients with opisthorchiasis, and patients with BA and opisthorchiasis co-occurred. A proposed down-regulation of immune response by higher level of IL10 and TGFB genes expression in patients with opisthorchiasis was revealed.

To elucidate the molecular mechanisms of O. felineus impact into phenotypic variability of allergic diseases in the opisthorchis endemic region, we studied 104 patients with opisthorchosis, 92 patients with atopic bronchial asthma, 52 patients with a combination of both diseases, and 120 healthy persons. Standard clinical, immunological, and genetic methods were used. An association of opisthorchis invasion with the improvement of lung function signs and bronchial hyperreactivity was found. It was established, that IL-4-dependent mechanisms of atopy were suppressed by O. felineus antigens, in particular due to hyperproduction of IL-10 and transforming growth factor-beta. However, IL-5-dependant mechanisms were supported. A phenomenology of the cytokine gene differential expression was established, disclosing the molecular basis of the immune system function in diseases with polar immune response in the helminth endemic region.

The aim was to estimate the epidemiological and pathogenetic correlation between allergic diseases and opisthorchiasis in the population of Tomsk and the Tomsk Region. The program was a cross-sectional epidemiological snap study based on two samples: village inhabitants ( n = 201; mean age 12,1 ± 3,4) and Tomsk inhabitants ( n = 196; mean age 30,16 ± 12,86). The epidemiological, clinical, parasitological, allergological, immunological, and statistical methods were used in the study. It has been found that allergic diseases affected about 40.9% of village patients with opisthorchiasis and 26,1% people without parasites ( р < 0.05). For Tomsk inhabitants, this proportion was 54,5 and 52,6%.