Haplotype Analysis of the NADPH Oxidase p22^phox Gene in Patients with Bronchial Asthma

Abstract

Background: Superoxide produced by airway epithelial and inflammatory cells may contribute to the pathogenesis of asthma. NADPH oxidase (an enzyme complex made up of 5 subunits) is a major source of superoxide in cells. We sought to elucidate the role of genetic variability in the gene encoding the p22^phox subunit of the NADPH oxidase (CYBA, 16q24.3) in asthma susceptibility by means of an association study of haplotypes based on 3 common single nucleotide polymorphisms (SNPs), –930A/G, 242C/T (H72Y) and 640A/G. Methods: SNPs were genotyped by PCR-RFLP methods in a cohort of age- and sex-matched subjects with bronchial asthma (n = 305) and healthy controls (n = 311). Haplotypes were constructed in silico using a Monte Carlo-based algorithm. Furthermore, association of SNPs with sensitization to selected allergens (total 15 tested by skin prick test positivity/negativity) was analyzed. Results: In a single locus analysis, SNPs 242C/T and 640A/G were marginally significantly associated with asthma (p = 0.036 and 0.036, respectively). SNP 640A/G showed a significant association with sensitization to 2 allergens tested (p_corr < 0.02). Haplotype analysis identified a total of 8 haplotypes with population frequencies from 0.07 to 0.22. Distribution of haplotypes significantly differed between cases and controls (omnibus p = 0.017, 10,000 permutations). In the post-hoc analysis, haplotype CYBA₃ (–930G/242T/640A) was associated with an increased risk of asthma (p_corr < 0.05; OR = 1.43, 95% CI 1.06–1.93). Conclusions: This study supports the hypothesis that genetic variability in the CYBA gene probably contributes to the susceptibility to bronchial asthma (or its related phenotypes) in our population.

Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

“…In particular, we confirmed a potential role in the pathogenesis of asthma for CYBA and CAT genes that was associated with asthma in Czech [60] and Canadian [61] populations, respectively. In addition, the associations of asthma with the IL5 C-703T polymorphism in Russians from the city of Tomsk [35] and IL1B −511C>T in the Canadian Asthma Primary Prevention Study [62] have been successfully replicated in our study.…”

Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation

“…24,39,40 NOX2 gene polymorphism, which may affect the production of ROS by leukocytes, is associated with different human diseases, including asthma, arthritis, stroke, and coronary artery disease. [41][42][43][44] It was recently reported that lack of NADPH oxidase activity markedly increased the severity of arthritis in a mouse model of arthritis. 45 How leukocyte NADPH oxidase contributes to tissue oxidant stress and regulates or facilitates inflammation in different tissue types is, therefore, an important question to ask if we are to elucidate the pathogenesis of these diseases.…”

The Serine Protease Inhibitor, 4-(2-aminoethyl) Benzene Sulfonyl Fluoride Hydrochloride, Reduces Allergic Inflammation in a House Dust Mite Allergic Rhinitis Mouse Model

“…Compound 4-(2-Aminoethyl) benzene sulfonyl fluoride hydrochloride (AEBSF) is an irreversible serine protease inhibitor with broad specificity (trypsin, chymotrypsin, plasmin, thrombin, kallikreins) and high affinity. AEBSF is a unique molecule that can inhibit serine proteases as well as NADPH oxidase, the primary enzyme responsible for catalyzing the production of reactive oxygen species in epithelial cells, inflammatory cells, and phagocytes 5. Due to these properties, we hypothesized that AEBSF might reduce allergic airway inflammation.…”