GSNO reductase and β₂-adrenergic receptor gene-gene interaction: Bronchodilator responsiveness to albuterol

Background: Short-acting inhaled β2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The β2-adrenergic receptor (β2AR) is the target for β2-agonist drugs. The enzyme, S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to β2-agonists. Objective: We hypothesized that there are pharmacogenetic interactions between GSNOR and β2AR gene variants that are associated with variable response to albuterol. Methods: We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these individuals for pharmacogenetic interaction between GSNOR and β2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants. RESULTS: Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3′UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (P=0.04-0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene-gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and β2AR gene variants and the response to albuterol in Puerto Rican (P=0.03), Mexican (P=0.15) and combined Puerto Rican and Mexican asthmatics (P=0.003). Specifically, GSNOR+17059*β2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response. Conclusion: Genotyping of GSNOR and β2AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma.