Haplotype Analysis of the NADPH Oxidase p22phox 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.