Roles of arginase variants, atopy, and ozone in childhood asthma

Background: Arginases; (encoded by ARG1 and ARG2 genes) might play an important role in asthma pathogenesis through effects on nitrosative stress. Arginase expression is upregulated in asthma and varies with T(H)2 cytokine levels and oxidative stress. Objective: We aimed to examine whether variants in these genes are associated with asthma and whether atopy and exposures to smoking and air pollution influence the associations. Methods: Among non-Hispanic and Hispanic white participants of the Children's Health Study (n = 2946), we characterized variation in each locus (including promoter region) with 6 tag single nucleotide polymorphisms for ARG1 and 10 for ARG2. Asthma was defined by parental report of physician-diagnosed asthma at study entry. Results: Both ARG1 and ARG2 genetic loci were significantly associated with asthma (global locus level P = .02 and .04, respectively). Compared with the most common haplotype within each locus, I ARG1 haplotype was associated with reduced risk (odds ratio [OR] per haplotype copy, 0.55; 95% CI, 0.36-0.84), and I ARG2 haplotype was associated with increased risk (OR per haplotype copy, 1.35; 95% CI, 1.04-1.76) of asthma. The effect of the ARG1 haplotype that was significantly associated with asthma varied by the child's history of atopy and ambient ozone (P-interaction = .04 and .02, respectively). Among atopic children living in high-ozone communities, those carrying the ARG1 haplotype had reduced asthma risk (OR per haplotype copy, 0.12; 95% CI, 0.04-0.43; P-heterogeneity across atopy/ozone categories = .008). Conclusions: ARG1 and ARG2 loci are associated with childhood asthma. The association between ARG1 variation and asthma might depend on atopy and ambient ozone levels. (J Allergy Clin Immunol 2009;123:596-602.)