M. A. Solodilova

Tobacco Smoking, Fruit and Vegetable Intake Modify Association Between -21A > T Polymorphism of Catalase Gene and Risk of Bronchial Asthma

Although oxidative stress is a cardinal feature of bronchial asthma, the role of interactions between environmental oxidant/antioxidant exposures and antioxidant genes in asthma aetiology has yet to be determined. The present study was conducted to investigate whether two common polymorphisms -21A > T and -262C > T of catalase (CAT) gene are associated with susceptibility to asthma in a Russian population and to test the hypothesis that the asthma risk attributed to CAT genotypes could be dependent on both oxidant (tobacco smoking) and antioxidant (fruit and vegetable intake) exposures. A total of 429 unrelated Russian individuals from Central Russia were recruited in the study, including 215 asthmatics and 214 sex- and age-matched healthy controls. Genotyping analysis for the CAT gene polymorphisms was performed by PCR-RFLP assays. The frequencies of both allele -21A (OR 0.73 95%CI 0.55–0.96 p = 0.03) and -21AA CAT genotype (OR 0.42 95%CI 0.23–0.76 p = 0.004) were higher among asthmatics than among healthy controls. The frequency of -21AA genotype of the CAT gene was significantly higher in patients with allergic (OR 0.47 95%CI 0.25–0.92 p = 0.024) and nonallergic (OR 0.32 95%CI 0.14–0.71 p = 0.004) asthma in comparison with controls (at the Bonferroni corrected p value less than 0.025). Polymorphisms -21A > T and -262C > T of the catalase gene were in a positive linkage disequilibrium (p < 0.0001). Smokers who carried -21AA genotype had an increased risk of nonallergic asthma (p = 0.002), whereas nonsmoker carriers of this genotype did not have the risk of any variant of the disease. Notably, no association of CAT genotype -21AA with asthma was found in high fruit and vegetable consumers, whereas low fruit and vegetable consumers (one time per day or less often) possessing this genotype were at increased risk of both allergic (p = 0.013) and nonallergic (p = 0.008) asthma. This is the first study reporting an association of polymorphism -21A > T of the catalase gene with allergic and nonallergic asthma. We also found, for the first time, that cigarette smoking and fruit and vegetable intakes have potentially inverse modifying influences on the asthma risk in individuals with -21AA CAT genotype and that the gene-environment interactions that were found support the biologic plausibility of catalase gene for the development of bronchial asthma.

Association analysis of C242T and A640G polymorphisms in the gene for p22phox subunit of NADPH oxidase with the risk of bronchial asthma: A pilot study

Genetic control of free radical oxidation, generation of reactive oxygen species, as well as of preoxidant and antioxidant balance in airway diseases, including bronchial asthma, is an important issue of the research in pulmonology. The present study is the first investigation of association between two common polymorphisms, C242T (exon 4) and A640G (3′ untranslated region), within the NADPH oxidase gene (CYBA) and the risk of bronchial asthma. Samples of asthma patients (n = 209) and healthy controls (n = 210) of Russian nationality were examined. Genotyping of the CYBA C242T and A640G polymorphisms was performed using polymerase chain reaction and restriction fragment length polymorphism. It was demonstrated that the frequency of heterozygous CYBA genotype A640G in bronchial asthma patient group was lower than that in control group (OR = 0.66; 95%CI, 0.45–0.97; P = 0.04). Separate analysis of different clinical pathogenetic variants of the disease showed that homozygous wild-type CYBA genotype 640AA was associated with the increased risk of allergic bronchial asthma (OR = 1.76; 95%CI, 1.07–2.90; P = 0.03), while heterozygous CYBA genotype A640G was associated with the decreased risk of this form of the disease (OR = 0.63; 95%CI, 0.41–0.96; P = 0.03). Thus, a new candidate gene for allergic bronchial asthma was discovered. Possible mechanisms of the involvement of CYBA in the development of asthmatic phenotype are discussed.

Analysis of common transforming growth factor beta-1 gene polymorphisms in gastric and duodenal ulcer disease: Pilot study

Background and Aim:  Transforming growth factor‐β1 (TGF‐β1) has been shown to be an important cytokine that plays a role in cell proliferation, differentiation, tissue injury repair and ulcer healing. The purpose of this pilot study was to investigate if common polymorphisms Leu10Pro, Arg25Pro and C‐509T within the TGF‐β1 gene are associated with susceptibility to gastric and duodenal ulcer disease in Russians.

CYP2E1 Gene Promoter Polymorphism -1293G>C Increases the Risk of Essential Hypertension in Men with Alcohol Abuse

We studied the association between of cytochrome P450 2E1 (CYP2E1) gene polymorphism and risk of essential hypertension development depending on alcohol drinking habit in unrelated men in Russian population (patients with essential hypertension and healthy volunteers). All participants were genotyped for four CYP2E1 gene polymorphisms -1293G>C (rs3813867), -1053C>T (rs2031920), 7632T>A (rs6413432), and 9896C>G (rs2070676) by PCR and restriction analysis. We found statistically significant associations between -1293C allele (OR=5.04, 95% CI=1.23-20.70, p=0.03) and -1293GC genotype (OR=5.36, 95% CI=1.28-22.50, p=0.03) with increased risk of essential hypertension in men. Stratified analysis on alcohol drinking habit showed that the presence of -1293C allele (OR=6.82, 95% CI=1.12-41.70, p=0.04) and -1293GC genotype (OR=7.61, 95% CI=1.2-48.4, p=0.03) in men with alcohol abuse increases the risk of essential hypertension. The obtained data suggest that excessive alcohol consumption and increased induction of cytochrome in the carriers of -1293C allele of CYP2E1 gene lead to generation of highly reactive free radical oxidation products. These processes induced oxidative stress and endothelial induction, which served as the pathogenetic basis for essential hypertension.

Genetic variation of myeloperoxidase gene contributes to atopic asthma susceptibility: a preliminary association study in Russian population.

Background. Recently, we have shown that both antioxidant and oxidant genes are proper candidates for asthma susceptibility genes. Objectives. In the present study we investigated whether a common polymorphism −463G > A in the promoter of myeloperoxidase (MPO) gene, an enzyme producing hypohalogenic oxidants, is associated with the risk of bronchial asthma. Methods. We studied 429 unrelated Russian subjects including 215 asthmatic patients and 214 sex- and age-matched healthy controls from Central Russia. The genotyping of the polymorphism −463G > A in the MPO gene was performed by the polymerase chain reaction and the restriction fragment length polymorphism assays. Results. It was found that a carriage of a −463A allele is associated with decreased risk of asthma (OR 0.64 95%CI 0.44–0.91, p = 0.013). Furthermore, variant genotypes (−463GA + AA) of the MPO gene were associated with decreased risk of asthma (OR adjusted by age, gender, and immunoglobulin E (IgE) level was 0.63 95%CI 0.42–0.95), but at a borderline statistical significance (Bonferroni corrected p = 0.017). Further analysis revealed that both a −463A allele and the −463GA/AA genotypes are significantly associated with decreased risk of atopic asthma (p = 0.01). No association of the −463G > A polymorphism of the MPO gene with non-atopic asthma has been revealed. We also found that the allele −463A (OR = 0.47 95%CI 0.27–0.81, p = 0.01) and the −463GA + AA genotypes (OR 0.43 95%CI 0.24–0.78, p = 0.005) are significantly associated with decreased risk of late-onset atopic asthma (the disease onset after 30 years). No association of both allele and genotypes of the polymorphism −463G > A of the MPO gene with early-onset of atopic and non-atopic asthma (the disease before 30 years) was seen. Conclusions. The results of this study provide novel insights into pathogenesis of bronchial asthma. We put forward a suggestion about a possible mechanism by which the −463G > A polymorphism of the MPO gene is involved into pathogenesis of asthma.

The Contribution of Genetic and Environmental Factors to Quantitative Variability of Erythrocyte Membrane Proteins in Primary Hypotension

Our previous studies have shown that, compared with healthy individuals, patients with primary arterial hypotension (PAH) have significant quantitative changes in erythrocyte membrane proteins. The purpose of the present study was to evaluate the contribution made by genetic and environmental factors to quantitative variation of erythrocyte membrane proteins in PAH. We studied 109 hypotensive patients, 124 normotensive subjects, 222 of their first‐degree relatives and 24 twin pairs by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. The decomposition of total phenotypic variance of erythrocyte membrane proteins to genetic and environmental components was performed on the basis of correlations among first‐degree relatives by the least squares method. The genetic dominance and shared environmental factors were found to influence the variability of cytoskeletal membrane proteins whose contents were changed in PAH. Furthermore, variations in α‐spectrin, actin and anion exchanger in hypotensives were substantially influenced by major gene and maternal effects. Ankyrin 2.1 and actin content was under the control of common underlying genes. Variations in membrane‐associated glutathione‐S‐transferase and tropomyosin were predominantly affected by polygenes. These findings suggest that the putative major genes with pleiotropic effects appear to be involved in the control of quantitative disorders of erythrocyte membrane proteins in primary hypotension.

Genetic and biochemical mechanisms of involvement of antioxidant defense enzymes in the development of bronchial asthma

Recent achievements in the understanding genetic and biochemical mechanisms of the involvement of antioxidant defense enzymes in the pathogenesis of bronchial asthma have been summarized and discussed in this review. We concluded that genetically determined abnormalities in the functioning of antioxidant defense enzymes may play a substantial role in the development of bronchial asthma. Variation in genes for antioxidant defense enzymes in combination with pro-oxidant effects of the environment are responsible for a imbalance between oxidant and antioxidant processes with the shift of the redox state towards increased free radical production and induction of oxidative stress in the respiratory system, thereby contributing to the pathogenesis of bronchial asthma.