Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype.

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.

An in-depth study of the associations between osteoarthritis- and osteoporosis-related phenotypes at different skeletal locations.

The relationship between OA and osteoporosis characteristics remains controversial. This study revealed that age-adjusted hand OA is associated with lower hand/arm BMD levels. Wrist fracture occurrence is associated with increased OA hand scores and low arm BMD. Conversely, age-adjusted knee and spine OA is associated with high spine, hip, and total BMDs. INTRODUCTION: Osteoarthritis (OA) and osteoporosis are two common musculoskeletal diseases which contribute a high burden of disability, yet assessments of their relationship remains controversial. The aim of this study was to clarify the association between bone mineral densities (BMD) of the hand, arm, spine, hip, and total body, and OA of the hand and knee and lumbar disc degeneration in two different ethnic groups. METHODS: Radiographic assessments of the hand, knee, and spine were collected and coded for joint space narrowing, osteophytes, and the Kellgren-Lawrence score from Chuvashian (n = 1504) and British (n = 2280) individuals. BMD measurements of standard skeletal sites were estimated by dual X-ray absorptiometry. Age- and familial-adjusted regression analyses were conducted to determine associations. RESULTS: Knee OA affection was positively associated with elevated hip, spine, and total body BMD levels (p < 0.001). Additionally, disc degeneration phenotypes showed significant positive associations with the hip, spine, and total BMD (p < 0.001). However, increased hand OA scores was significantly negatively correlated with arm and hand BMD measurements in males and females in both samples (p < 0.001). Additionally, higher hand OA scores were significantly associated with wrist fracture. CONCLUSIONS: We discovered a clear pattern of association between hand OA and low hand and arm BMD, with increased risk of wrist fracture, as well as reproducing previous associations between knee and spine OA and elevated spine, hip, and total body BMD. It appears that hand OA manifests differently in comparison to hip and knee OA.

Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium.

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<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.

[The frequency and spectrum of cytogenetic anomalies in employees of Siberian Group of Chemical Enterprises].

The results of the study of frequency and spectrum of cytogenetic anomalies in 657 healthy employees of the main facilities of the Siberian Group of Chemical Enterprises exposed to external, internal and combined irradiation are presented. No dependence between age and chromosome aberrations frequency was revealed. Chronic external exposure appeared to be the main factor of induction of chromosome aberrations. The frequency of aberrant cells, chromosome type aberrations, paired fragments and rings was statistically significantly higher in employees exposed to external irradiation as compared to persons exposed to combined irradiation. A nonlinear dependence the dose of irradiation and frequency of chromosome aberrations was revealed. A statistically significant decrease of prevalence of aberrant cells, aberration of chromatid and chromosome type was established in employees exposed to irradiation at a dose range of > 0-10 mSv compared to the control group. This agrees with the phenomenon of radiation hormesis. A significant increase of the frequency of chromosome aberrations was not observed at doses below > 40 mSv. In employees exposed to irradiation at a dose range > 40-100 mSv, a statistically significant increase of frequencies of aberrant metaphases, aberrations of chromatid and chromosome types was established. Same was found for dicentrics at dose range of >100-200 mSv. This supports a well known linear threshold model. Dose-effect curve has a plateau at doses ranged from 100 to 500 mSv.

[Composition of microorganism community in the airways of patients with chronic obstructive pulmonary disease].

This review summarizes results of research on the composition of microorganism community in the airways of patients with chronic obstructive pulmonary disease. Modern technologies for molecular genetic identification of microorganisms provide a deep insight into the microbiota of patients with chronic broncho-obstructive diseases for the better understanding of bronchopulmonary pathology in man and effect of microbiotic communities on the clinical course of diseases and formation of resistance to antibiotics.

[The role of genetic factors in the development of chronic dust bronchitis in workers of coal mining enterprises of Kuzbass].

The distribution of genotypes of HP, GC, EsD, AsP and polymorphisms GSTT1 (GST-theta1) and GSTM1 (GST-micro1) and NOS3 (polymorphism VNTR4) in miners with chronic dust bronchitis, and in those without this occupational disease has been studied The carriers of genotypes of genotypes EsD 1-2, AsP bb were shown to be more prone to develop chronic dust bronchitis. Endogenous factors of resistance to the disease are the genotypes GC 1-1, EsD 1-1, AsP bc.

[Association of polymorphism Rs6737848 in the Socs5 gene with bronchial asthma].

AIM: To investigate the role of polymorphic variants of immune-response modifying genes in predisposition to asthma. PATIENTS AND METHODS: The analysis of restriction fragments length polymorphism was used to investigate 10 single-nucleotide polymorphisms: IFNG rs2069705, IFNGR2 rs17880053, IL4 rs 2070874, IL4RA rs 1805010, GATA3 rs10905277, TBX21 rs11652969, PIASY rs3760903, PIAS3 rs12756687, STATS rs16967593, and SOCS5 rs6737848 in 106 asthma patients and 115 healthy people. RESULTS: The rs6737848 SOCS5 polymorphism was significantly associated with asthma in additive model (p = 0.05, OR = 0.338, 95% CI 0.158-0.723) and in dominant model (p = 0.02, OR = 0.284, CI 0.126-0.638). None of the polymorphisms of the studied genes was associated with total IgE levels. CONCLUSIONS: This is the first report on the association of rs6737848 SOCS5 with asthma.

[Molecular and pharmacogenetic mechanisms of severe asthma].

This review summarizes the results of studies to identify the dominant mechanisms of development and persistence of inflammation in severe asthma and results of pharmacogenetic studies of determination response to drugs. These mechanisms could potentially be used for diagnostic purposes and become the new targets of asthma therapy. Pharmacogenetic information will enable the use of a personalized approach to the asthma management which will adjust the therapy technology and increase the possibility of achieving disease control.

[Effect of additional disease (comorbidity) on association of allergic rhinitis with KCNE4 gene rs12621643 variant].

Analysis of association of allergic rhinitis with the KCNE4 gene rs12621643 variant was conducted in Russian residents of Western Siberia (taking into account comorbidity with bronchial asthma). It was found that, among individuals without bronchial asthma, the frequencies of the KCNE4*G allele and KCNE4*G/G genotype are significantly higher in patients with rhinitis compared to individuals without it. At the same time, no association of rs12621643 with rhinitis was detected in the group of individuals with bronchial asthma. The data obtained indicate the association of the KCNE4 gene variability with allergic rhinitis, although the effect of this gene relative to the development of the disease can be leveled against a background of the manifestation of another atopic disease.

[The estimate of association between gene polymorphisms and the frequency and spectrum of cytogenetic abnormalities in the cohort of Siberian Group of Chemical Enterprises employees exposed to professional irradiation (microarray studies)].

The results from the research into the association between polymorphisms of genes-candidates for individual radiosensitivity and the frequency and spectrum of cytogenetic abnormalities are analyzed. The study was conducted among Siberian Group of Chemical Enterprises healthy employees exposed to professional irradiation in a dose range of 100-300 mSv. Genotyping of DNA samples from 96 employees was carried out by oligonucleotide microarray: "Cancer_SNP_Panel GT-17-211" ("Illumina") containing 1, 421 SNP-markers (Single Nucleotide Polymorphisms) of 406 genes. The standard cytogenetic analysis was performed in the entire examined group. We have also analyzed the association of these SNP with the frequencies of aberrant cells and following chromosomal aberrations: single chromatid fragments, chromatid exchanges, paired fragments, dicentric, ring and frequencies, translocations. We have found that 40 SNP (rs1800389, rs1051690, rs2392221, rs1041163, rs2114443, rs6083, rs1760904, rs4986894, rs488133, rs7462102, rs11249938, rs34206126, rs33945943, rs34324628, rs5742694, rs978458, rs5742667, rs2373721, rs2162679, rs889162, rs2233679, rs2010457, rs2873950, rs1574154, rs10934500, rs4688046, rs10934503, rs4624596, rs2288729, rs4227, rs1367696, rs751087, rs1269486, rs1149901, rs1800404, rs887477, rs696405, rs751087, rs81 92284, rs312016) are associated with the frequency of different types of chromosomal abnormalities (p-value with FDR of Benjamini-Hochberg--equal less than 0.05). 24 SNP (underlined) are associated with more than one type of chromosome abnormalities. In the future, we are going to confirm the results in further studies on the cohort of more than 600 persons.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

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. 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 DENND1BSNP. 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.

NMDA receptor genotypes associated with the vulnerability to develop dyskinesia.

Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl-D-aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose-dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism.

[Genome-wide association study of allergic diseases in Russians of Western Siberia].

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

[Syntropic genes of allergic diseases].

Common (syntropic) genes of allergic diseases (ADs) HLA-DQB1, HLA-DRB1, IL4, IL4RA, MS4A2, HLA-DQA1, LTC4S, IL13, IL10, and TGFBL have been identified on the basis of information from the HuGENet internet database. The functional sphere of competence 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 ofADs confirms their accepted clinical classification.

Genetic view on the phenomenon of combined diseases in man.

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 19th century through the "arthritismus" doctrine. In the first half of the 20th 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. The 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 cardiovascular diseases.

[The evaluation of association between polymorphisms of DNA excision repair enzyme genes and risk of malignant tumors development in Siberian Group of Chemical Enterprises workers].

There was analyzed single nucleotide polymorphisms of DNA excision repair enzyme genes hOGG, XPD, XPG, XRCC1 in 98 Siberian Group of Chemical Enterprises cancer patients and 148 healthy donors. No association was observed between the analyzed polymorphisms and malignant tumors in both control and subgroup (under study) of persons exposed to occupational ionizing radiation. Heterozygosis for the genes hOGG and XPD was found to be a protective factor to malignant tumors in exposed persons: the odds ratio = 0.42 (95% CI 0.18-0.98; p = 0.044) for the 326Ser/Cys genotype of the hOGG gene and 0.48 (95% CI 0.23-0.99; p = = 0.047) the 751Lys/Gln genotype of the XPD gene. The data obtained show a possible modifying role of the hOGG and XPD gene polymorphisms for malignant tumors risk in exposed persons.

[Regional medico-dosimetric register (RMDR) is a model for evaluation of long-term "low" dose ionizing radiation effects on Siberian group of chemical enterprises main production personnel].

Medico-dosimetric register is an optimal model of epidemiological studies on evaluation of ionizing radiation effects. Regional medico-dosimetric register (RMDR) is a system of interrelating information blocks including data on Siberian Group of Chemical Enterprises (SGCE) personnel. At present SGCE personnel and Seversk residents RMDR database includes information on 138496 persons, 65538 of which are SGCE workers. SGCE personnel and Seversk residents RMDR is a scientific base for researches with the aim of evaluating long-term ionizing radiation effects in a "low" dose range. Information on mortality and morbidity rate as well as "thematic" registers of the main diseases potentiates in evaluating the spectrum of somatic stochastic effects and radiogenic risks in SGCE workers and Seversk residents as well as their offsprings. A practical significance of RMDR database is the formation of the main diseases "risk" groups depending on definite risk factors in certain groups that provides targeted diagnostic and preventive therapy both among high-dose establishments' workers and residents living near-by.

[Association of immune system gene polymorphisms with quantitative features which are pathogenetically important in chronic viral hepatitis].

Association study was performed for genetic polymorphisms IL4 C(-590)T, IL4RA Ile50Val, TNF G(-308)A, to estimate their effect on quantitative features which are pathogenetically important for chronic viral hepatitis course, i.e. levels of IL4, IL10, IL12, tumor necrosis factor alpha, fibronectin, collagenase, protease inhibitors, macroglobulines, elastases, free and protein-bound hydroxyproline. It has been shown that A allele of TNF G(-308)A polymorphism is associated with decreased TNF-alpha, increased IL4 and IL12, as well as with low level of protein-bound hydroxyproline. In addition, association of CT genotype of IL4 C(-590)T polymorphism and high level of protein-bound hydroxyproline has been identified.

[Genetics factors determining predisposition to chronic course of virus hepatitis and fibrosis in liver].

Polymorphic variants of several genes IL4 C(-590)T, IL4RA Ile50Val, TNF G(-308)A were studied for their association with extent of the disease chronization which is marked by hepatic fibrosis stage. Gradual decrease in A allele frequency of polymorphic marker G(-308)A in TNF gene, from patients with weak fibrosis to patients with cirrhosis. Group of patients with weak fibrosis was characterized by higher frequency of A allele (24.5%) comparing with patients with moderate and pronounced fibrosis (13.4%) and cirrhosis (8.7%). Differences in heterozygous genotype frequencies of IL4 C(-590)T were found between patients with cirrhosis (68.2%) and groups of patients with moderate and marked fibrosis (39.1%).

A pilot screening of prevalence of atopic states and opisthorchosis and their relationship in people of Tomsk Oblast.

The study was aimed to estimate the relationship between the prevalence of allergic disease and helminth invasion by the trematode Opisthorchis felineus in rural and urban populations of Tomsk Oblast (West Siberia, Russia). Two hundred and one people from Kargasok village of Tomsk Oblast and 196 from the city of Tomsk were screened for the presence of atopy and O. felineus invasion. Opisthorchosis was found in 66 participants (32.8%) from Kargasok and in 22 people (11.2%) from Tomsk. Atopic diseases were more common in the urban population than in the rural: 52.8 and 31.4%, respectively. Positive skin-prick tests were significantly higher in the urban population than in rural people: 83.2 vs 24.4%, respectively. It was found that in the city, the presence of antibodies to O. felineus negatively correlates with the atopic sensitization by skin-prick tests. However, in the village, opisthorchosis was positively associated with atopic diseases. The data obtained confirm the negative association of rural lifestyle and atopic diseases prevalence and indicate that O. felineus invasion might be a modifying factor of this relationship in Tomsk Oblast.