The role of polymorphic variants of arginase genes (ARG1, ARG2) involved in beta-2-agonist metabolism in the development and course of asthma.

Asthma is a common severe disease of the respiratory tract, it leads to a significant impairment in the quality of a patient's life unless effectively treated. Uncontrolled asthma symptoms are a cause of disease progression and development, they lead to an increase in the patient's disability. The sensitivity to asthma therapy largely depends on the interaction of genetic and epigenetic factors, which account for about 50-60 % of variability of therapeutic response. Beta-2-agonists are some of the major class of bronchodilators used for asthma management. According to published data, allelic variants of the arginase ARG1 and ARG2 genes are associated with a risk of asthma development, spirometry measures and efficacy of bronchodilator therapy. High arginase activity results in a low level of plasma L-arginine and in a decrease in nitric oxide, and, as a result, in an increase in airway inflammation and remodeling. Arginase genetic polymorphisms (rs2781667 of the ARG1 gene, rs17249437, rs3742879, rs7140310 of the ARG2 gene) were studied in 236 children with asthma and 194 unrelated healthy individuals of Russian, Tatar and Bashkir ethnicity from the Republic of Bashkortostan. Association analysis of the studied polymorphisms with asthma development and course, the sensitivity to therapy in patients was carried out. It was found that the rs2781667*C allele of the ARG1 gene is a marker of an increased risk of asthma in Tatars. In Russians, the association of rs17249437*TT and rs3742879*GG genotypes of the ARG2 gene with a decrease in spirometry measures (FEV1, MEF25) was established. In Russians and Tatars receiving glucocorticoid monotherapy or combination therapy, the association of the rs17249437*T allele and rs17249437*TT genotype of the ARG2 gene with a partially controlled and uncontrolled course of asthma was shown.

[Association of Polymorphic Variants of Gene MUC19 with Asthma in Russians According to the Results of a Genome-Wide Study].

Asthma is a heterogeneous multifactorial disease that is characterized in most cases by chronic respiratory tract inflammation. We carried out a GWAS in order to identify susceptibility genes for asthma in individuals of different ethnic backgrounds. The study sample consisted of 358 unrelated patients with asthma (160 Russians, 125 Tatars, and 73 Bashkirs) and 369 individuals of a control group (152 Russians, 117 Tatars, and 100 Bashkirs). DNA samples were genotyped with an Illumina human610 quad array (Illumina) as part of the project GABRIEL. Replication of the results of genome-wide analysis was carried out on an additional independent sample of 310 asthma patients (132 Russians, 105 Tatars, and 73 Bashkirs) and 310 individuals in a control group (131 Russians, 106 Tatars, and Bashkirs 77). Genome-wide analysis showed an association of asthma in Russians with the polymorphic loci of gene MUC19 (12q12) encoding gel-forming mucin 19. The highest level of association with asthma was found in rs2933346, which is located in intron 52 of this gene (p = 2.59 x 10(-6)). Seven polymorphic loci of gene MUC19 (rs1492313, rs2588401, rs2588402, rs2638863, rs2638864, rs1352940, and rs2933373), which are in close linkage disequilibrium among themselves and rs2933346, are associated with asthma with the same p-value (p = 4.96 x 10(-6)). The replicative study of rs1492313 in the independent sample of individuals confirmed the presence of the association of the polymorphic loci of this gene with the development of asthma in Russians. According to our data, the association of polymorphic variants of gene MUC19 with asthma has not been previously identified in any study. Our results indicate the important role of polymorphic variants of gene MUC19 in the formation of a predisposition to the development of asthma in individuals of Russian ethnicity.

[Association of polymorphisms in toll-like receptor genes with atopic dermatitis in the Republic of Bashkortostan].

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease developing as a result of the interaction between genetic predisposition and environmental factors. Considerable role in allergic diseases development is played by polymorphisms of genes of pattern-recognition receptors (PRR) which are capable of recognizing conservative standard molecular structures (patterns) unique for large pathogen groups. In this study polymorphic variants of PRR genes--Toll-like receptors (TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, TLR10), NOD-like receptors (NOD1, NOD2), lipopolysaccharide receptor CD14 gene, and C11orf30 and LRRC32 genes, located in 11q13.5 region, have been investigated in AD patients and control subjects from the Republic of Bashkortostan. An association of TLR1 (rs5743571 and rs5743604), TLR6 (rs5743794) and TLR10 (rs11466617) with AD was found. Our results confirm an important role of the innate immune system in the pathogenesis of AD and the significance of polymorphisms within the Toll-like receptor 2 subfamily genes in AD development.

[Genome-wide association study of bronchial asthma in the Volga-Ural region of Russia].

Bronchial asthma is a chronic inflammatory respiratory disease that is caused by the complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between SNPs within 17q12-21 genomic region and childhood bronchial asthma in individuals of European descent. Association with this genomic region was then replicated in a number of independent samples of European and Asian descent. Here we report results of the first genome-wide association study of bronchial asthma in the Volga-Ural region of Russia. The present study includes 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnic origin (Russians, Tatars and Bashkirs). Genotyping of DNA samples was carried out using the Illumina Human610 quad array as a part of GABRIEL project (contract from the EC No LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550915 SNPs genotyped in 330 cases and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed statistically significant association with bronchial asthma (p < or = 4.79 x 10(-7)). SNP rs7216389 with the strongest evidence for association (p = 1.01 x 10(-7)) is located within the first intron of the GSDMB gene. Evidence for association was stronger with childhood-onset asthma (p = 1.97 x 10(-6) for SNP rs7216389) compared to late-onset asthma (p = 1.8 x 10(-4) for SNP rs7216389). Our replication study using three SNPs within GSDMB gene confirmed association with only childhood-onset asthma. In summary, these results suggest an important role for genetic variants within 17q12-q21 region in the development of bronchial asthma in the Volga-Ural region of Russia.

[Association of xenobiotic-metabolizing gene polymorphisms with childhood atopic diseases in Russian patients from the Republic of Bashkortostan].

Enzymes of biotransformation system involved in the metabolism of exogenous and endogenous compounds are effective mechanism of protection from negative environmental factors. Decreasing activity or insufficient synthesis of biotransformation system enzymes caused by genetic polymorphism form the risk of various complex diseases, including atopic. Using allele-specific hybridization on the biochip the frequencies of xenobiotic-metabolizing gene polymorphisms in Russian children with bronchial asthma, allergic rhinitisand healthy donors from the Republic of Bashkortostan have been determined. The analysis of polymorphisms in CYP1A1, GSTT1, GSTM1, NAT2, MTHFR, CYP2C9 and CYP2C19 genes didn't reveal any association with atopic diseases. The frequencies of CYP2D6*1934G/G genotype and CYP2D6*1934G allele were significantly higher among boys with rhinitis symptoms than in control group.

[Analysis of mutations and haplotypes of polymorphic markers in patients with Wilson-Konovalov disease from Bashkir]. / Analiz mutatsii i gaplotipov polimorfnykh markerov u patsientov s bolezn'iu Vil'sona-Konovalova iz Bashkirii.

Mutations of the Wilson disease (WD) gene were studied in patients from Bashkortostan. Four mutations were identified: His1069Gln, 3402delC, Glu1064Lys, and 3559 + 1G-->T. The latter mutation was described for the first time. Mutation His1069Gln was found to be the most prevalent in Bashkortostan; its frequency was 43.5%. The associations of the mutations found with the haplotypes for polymorphic loci D13S316, D13S133, and D13S228 were studied. The mutations were found to be linked with specific haplotypes, and the study of polymorphic haplotypes can therefore facilitate the search for mutations in the gene for WD. The results of the molecular genetic study of WD can be used for direct and indirect DNA diagnostics of this disease in Bashkortostan.