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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

The structure of diseases in humans is heterogeneous, which is manifested by various combinations of diseases, including comorbidities associated with a common pathogenetic mechanism, as well as diseases that rarely manifest together. Recently, there has been a growing interest in studying the patterns of development of not individual diseases, but entire families associated with common pathogenetic mechanisms and common genes involved in their development. Studies of this problem make it possible to isolate an essential genetic component that controls the formation of disease conglomerates in a complex way through functionally interacting modules of individual genes in gene networks. An analytical review of studies on the problems of various aspects of the combination of diseases is the purpose of this study. The review uses the metaphor of a hermeneutic circle to understand the structure of regular relationships between diseases, and provides a conceptual framework related to the study of multiple diseases in an individual. The existing terminology is considered in relation to them, including multimorbidity, polypathies, comorbidity, conglomerates, families, “second diseases”, syntropy and others. Here we summarize the key results that are extremely useful, primarily for describing the genetic architecture of diseases of a multifactorial nature. Summaries of the research problem of the disease connection phenomenon allow us to approach the systematization and natural classification of diseases. From practical healthcare perspective, the description of the disease connection phenomenon is crucial for expanding the clinician’s interpretive horizon and moving beyond narrow, disease-specific therapeutic decisions.

Aim. To analyze risk factors in the group of patients with Parkinson’s disease (PD) and compare them with the literature data.Materials and methods. The study included 439 patients with PD and 354 controls, comparable by gender and age. For each individual, a registration card was filled in containing demographic, epidemiological, clinical, and neuropsychological data. The severity of the disease was studied according to the MDS-UPDRS scale; the stage of PD was determined according to the Hoehn and Yahr scale. Cognitive functions were assessed by the MoCA test and MMSE. The length of the (CAG)n repeat region in the HTT gene was determined using fragment analysis on the ABI 3730 DNA analyzer. The obtained results were analyzed using GeneMapper Software v4.1 (Applied Biosystems, USA).Results. When comparing patients with PD and the control group, the odds ratio (OR) for PD in individuals with traumatic brain injury was 3.13 (95% confidence interval (CI): 2,27–4.34; p = 4.94 × 10–13), which showed the significance of this risk factor for PD. Consumption of coffee in the anamnesis distinguished the group of PD patients from the control group (OR = 0.41 (95% CI: 0.30–0.56); p < 0.0001), confirming its neuroprotective effect. Analysis of the variability in the length of the (CAG)n repeat regions in the HTT gene showed that patients whose genotype contained an allele with 17 repeats in combination with any allele other than an allele containing 18 repeats had a protective effect (OR = 0.50 (95% CI: 0.27–0.92); p = 0.025). All genotypes containing an allele with 18 repeats were predisposed to PD (OR = 2.57 (95% CI: 1.66–4.28); p = 0.007). The predisposing effect of the allele to PD, unrelated to the expansion of CAG repeats in the HTT gene, was revealed for the first time.Conclusion. Traumatic brain injury and the allele with 18 CAG repeats in the HTT gene are risk factors for PD. Coffee consumption can be attributed to protective factors in relation to PD.

Background. Approximately 5–10 % of cases of Parkinson’s disease (PD) are monogenic, in other cases the pathology has a multifactorial etiology. One of recognized pathogenetic pathways of PD is mitochondrial dysfunction, in particular the accumulation of damage in mitochondrial DNA. Hence, the genes of DNA repair proteins are promising candidate genes for multifactorial forms of PD.The aim. To study the involvement of genes of DNA repair proteins in the development of Parkinson’s disease.Materials and methods. The associative analysis was carried out while comparing a group of patients with PD (n = 133) with a Tomsk population sample (n = 344). SNaPshot analysis was used to study 8 SNPs in genes of DNA repair proteins (rs560191 (TP53BP1); rs1805800 and rs709816 (NBN); rs473297 (MRE11A); rs1189037 and rs1801516 (ATM); rs1799977 (MLH1); rs1805321 (PMS2)).Results. Common alleles and homozygous rs1801516 genotypes in the ATM gene predispose the development of PD (odds ratio (OR) – 3.27 (p = 0.000004) and OR = 3.46 (p = 0.00008) for risk alleles and genotype respectively) and rs1799977 in the MLH1 gene (OR = 1.88 (p = 0.0004) and OR = 2.42 (p = 0.00007) respectively); heterozygotes have a protective effect (OR = 0.33 (p = 0.0007) and OR = 0.46 (p = 0.0007) for ATM and MLH1, respectively). The rare rs1805800 allele in the NBN gene (OR = 1.62 (p = 0.019)) and a homozygous genotype for it (OR = 2.28 (p = 0.016)) also predispose to PD. Associations with PD of the ATM, MLH1, NBN genes were revealed for the first time.Conclusion. Mitochondrial dysfunction is one of the key factors in the pathogenesis of PD, while at least two of the three protein products of associated genes are involved in the development of mitochondrial dysfunction. Accordingly, it can be assumed that associated genes are involved in the pathogenesis of PD precisely through mitochondrial dysfunction.

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.

Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disease. Its molecular cause is a cytosine-adenine-guanine (CAG) trinucleotide repeat dynamic expansion in the huntingtin (HTT) gene. Alleles with 36–39 CAG-repeats are incompletely penetrant, as individuals might develop symptoms but typically with a later age of onset. When repeats are equal or greater than 40, the symptoms of the disease occur. It is considered that CAG-repeats in the “intermediate” alleles (27–35 repeats) also cause the symptoms of the HD.We present here the case of a patient who has clinical phenotype and family history of Parkinson’s disease (PD), but 27 CAG-repeats. The feature of this patient is early development of non-motor manifestations such as cognitive impairment, psychotic disorders, early dystonia in a hand, camptocormia and poor response to levodopa. It is believed that the intermediate allele of HTT gene might modify the clinical phenotype of PD in this patient.

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.

Non-motor symptoms are an essential manifestation of the clinical picture of Parkinson's disease (PD). This literature review is devoted to the study of recent advances in the field of clinical and pathophysiological aspects of the non-motor manifestations of Parkinson's disease.Aim. The aim was to study and generalize the wide range of non-motor manifestations of PD and their features in this pathology, and to reveal the pathophysiological link between motor and non-motor manifestations of the disease and the role of the neurodegenerative process in the clinical picture of PD.Materials and methods. Keywords (Parkinson's disease, non-motor symptoms, apathy, anxiety, depression, sleep disorder, pain) search in the Web of Science, Core Collection, Scopus, Pubmed databases.Results. Knowledge about the presence of PD non-motor symptoms, characteristics of their manifestations improve their diagnosis and help to choose the correct treatment strategy. This survey comprises nonmotor manifestations of PD, such as: mood disorders (apathy, anxiety, depression), impulse control disorders (dopamine disregulation syndrome), sleep disorders (insomnia, excessive daytime sleepiness, bouts of sleepiness, conduct disorder in REM phase of sleep), autonomic disorders (constipation, enuresis, thermoregulatory dysfunction, cardiovascular disorders, orthostatic hypotension), and cognitive impairment.

Background: Numerous studies have shown a link between genes involved in the immune response and infertility and miscarriage. The most significant associations have been established for the cytokine genes (IL1B, IL6, IL10, IL18), chemokine genes (CXCL9, CXCL10, CXCL11), and genes of the major histocompatibility complex HLA II class (DQA1, DQB1, DRB1). HLA genes are associated with celiac disease, a genetically determined autoimmune disorder, where male and female reproduction impairment is one of the symptoms. Aim: To assess the prevalence of polymorphic variants of the immune response genes (HLA: DQA1 DQB1, DRB1; TNF, IL10, CXCL10) in patients with reproduction disorders. Materials and methods: This pilot study involved assessment of the following gene polymorphisms: IL10 (rs1800872), TNF (rs1800629), CXCL10 (rs4386624), and HLA class II (DQA1, DQB1, DRB1) in couples (n = 220) with reproduction disorders (infertility and miscarriage). Genotyping was performed by real-time polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The genotypes and alleles population data were used for comparison with the studied variants of the genes IL10 (rs1800872), TNF (rs1800629), and CXCL10 (rs4386624). Differences in the prevalence of alleles and genotypes were assessed by χ2 test. The differences were considered significant at p < 0.05. Haplotype diversity was calculated by the Arlequin software, version 3.5.x. Results: Compared to the populational data, there was significant re-distribution of the genotypes and alleles to the TNF gene (rs1800629) variant in men with impaired reproductive functions. No differences were found for other gene variants studied. The frequency of HLA class II gene (DQA1, DQB1, DRB1) haplotypes associated with celiac disease (DQ2 and DQ8) in the study sample was 23.8%. Conclusion: The results indicate the important role of genes associated with celiac disease in the development of reproduction disorders.

The articles presents results of associative study of pulmonary tuberculosis and 17 genes with the wide competence field, which products are informative in relations to development of multi-factorial diseases of various etiology. The biggest number of associations was found out to the gene of NOS3 (in particular with rs1799983) – they were registered as associations with pulmonary tuberculosis in general (p = 0.003), and with its clinical forms (p = 0.006), tissue destruction level (p = 0.029), endophenotypes (0.002 ≤ p ≤ 0.033 for various clinical manifestations). The following combinations of genotypes of VNTR/rs1799983 are generally associated with studied pathology (gene of NOS3), rs3746190/rs11575926 (gene of IL12RB1), rs909253/rs1800629 (gene LTA/TNF). Moreover the following polymorphous variants of genes are associated with qualitative and quantitative signs of pulmonary tuberculosis: TNF, LTA, TNFRSF1B, IL12RB1, IFNGR2, ADRB2, IL4R, GNB3. The associative study of genes of GNB3, PPP3R1, GATA4 with tuberculosis was conducted for the first time.

Antioxidant activity (AOA) was measured in 185 inhabitants of the town of Seversk (members of 43 families and unrelated individuals). AOA was defined on the ability of a blood plasma to reduce an output of products, reacting with thiobarbituric acid in the model system «lecithine-Fe2 +-ions». Polymorphism of gastrointestinal glutathione peroxidase (GPX2) gene (two-allelic dinucleotide (TC)n repeat polymorphism) was investigated in 208 individuals. The presence of seasonal changes was revealed and no influences of sex and age on AOA in the considered group were shown. Approximately 50% variance in total AOA was due to the additive effects of genes. No statistical significant association between genetic variability of GPX2 and AOA variation was revealed. Estimation of GPX2 genetic variability contribution to AOA level was 2.53%.

The activating research interest in the problem of tuberculosis development is due to the increase in cases of drug resistance, coinfection with HIV and hepatitis, and the lack of an effective vaccine. However, the pathogenesis of tuberculosis remains insufficiently studied at present. A significant role is assigned to hereditary factors, as the majority of those infected with Mycobacterium tuberculosis remain resistant to tuberculosis, and only in 5—15% of cases does infection lead to the development of the disease. Despite a long history of research of genetic factors of susceptibility to tuberculosis infection — from the search for monogenic forms of immune dysfunction, associations of individual tuberculosis susceptibility genes, to the analysis of genome-wide associative studies and the assessment of the characteristics of the transcriptional profiles of patients, — the problem of obtaining clinically significant results for the identification and monitoring of risk groups remains particularly acute. The search of differentially expressed genes in groups with different status of the disease (non-infected, latent tuberculosis infection, presymptomatic state, active tuberculosis, recovery from tuberculosis, non-tuberculosis infection) led to identification of a large number of data which is not overlapped in different compared groups, different ethnic groups, in the studies of the whole blood and cellular models. Merging this wealth of data followed by its reanalysis helps to verify and update results. However, there still is a large number of questions concerning our understanding of the functioning of the human organism under the influence of M. tuberculosis. In recent years, new approaches have been used to develop test systems for the diagnosis of various forms of the disease. The review considers up to date results of expression studies of susceptibility to tuberculosis, namely, objects and approaches of research changing over time, forms of the host response to the mycobacteria infection studied, the influence of different factors on the results.