Recent work by Que et al

Recent work by Que et al with mouse models implicates GSNOR in the cause of asthma. GSNOR is expressed in multiple cell types in the lung, including airway epithelial cells and infiltrating leukocytes. After exposure to ovalbumin, GSNOR activity increased in airway lining fluid, perhaps reflecting its release from injured epithelial or inflammatory cells. After ovalbumin challenge, increased activity of GSNOR catalyzes the increased breakdown of endogenous S-nitrosothiols, which thus become depleted in the human asthmatic airway lining fluid.2, 7, 8 Decreased concentration of S-nitrosothiols in the airways contributes to bronchoconstriction. GSNOR knockout mice do not experience bronchoconstriction after administration of methacholine, a cholinergic agonist. When GSNOR is absent, S-nitrosothiol levels remain increased, contributing to decreased airway hyperresponsiveness in the knockout mice. Notably, in the face of ovalbumin challenge, they experience airway inflammation but not airway hyperresponsiveness. Furthermore, tracheal rings from GSNOR knockout mice repeatedly treated with isoproterenol, a β2-adrenergic agonist and airway dilator, maintained their responsiveness, whereas those from wild-type mice demonstrated a decrease in responsiveness after treatment. S-nitrosothiol homeostasis, modulated by GSNOR, regulates both basal airway tone and airway hyperresponsiveness to bronchoconstrictor and allergen challenges. Accelerated S-nitrosothiol turnover catalyzed by GSNOR is not only relevant to rodent airway hyperresponsiveness2, 35 but also to increased bronchial smooth muscle tone in human asthma.8, 11, 33 The 2 SNPs that we found to be associated with Rosiglitazone maleate (rs28730619 and rs1154404) are in moderate linkage disequilibrium ( = 0.35) with each other. Homozygotes for the most common GSNOR haplotype (GTCGG), which contained the major T allele of rs1154404 and the minor G allele of rs28730619, were at increased asthma risk. This result was consistent with the single SNP findings but did not clearly distinguish the relative importance of these 2 SNPs. These SNPs have not been studied for functional significance, and there is no clear basis to predict direct effects on GSNOR production and activity. Given that neither SNP is clearly functional, it is reasonable to speculate that there might be linkage disequilibrium with a functional SNP in this gene or outside. Notably, the tagging SNP rs1154404, located in intron 1, is in virtually complete linkage disequilibrium ( = 0.99) with 2 adjacent promoter SNPs, rs2602899 and rs2851301, in a potential nuclear factor κB binding site.36, 37 Although speculative, carrying the minor allele for these 2 promoter SNPs might result in the loss of the potential nuclear factor κB binding site and therefore could reduce GSNOR production, leading to increased levels of S-nitrosothiols and thus protection from airway hyperresponsiveness. In theory this schema could explain the association of rs1154404 with decreased risk of childhood asthma. We did not genotype these 2 promoter SNPs directly for several reasons: they are next to each other, which will affect the genotyping accuracy; they are not tagging SNPs based on linkage disequilibrium criteria; and genotyping these 2 SNPs will not provide additional information because they are essentially in complete linkage disequilibrium with our tagging SNP, rs1154404. Resequencing data from the National Institute of Environmental Health Sciences Environmental Genome Project indicates a distinct polymorphic pattern of the GSNOR gene in Asian subjects compared with Hispanic, European, and especially African subjects. This difference is consistent with the hypothesis of an African origin for humans. The Asian sample only has 3 SNPs with minor allele frequencies higher than 10%. One of these 3 common SNPs is rs28730619, which was associated with asthma in our Mexican population. Therefore in an Asian population one might be able to test the genetic effect of rs28730619 in the absence of common polymorphisms found in other populations.