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Novel Regulators of β2-adrenergic Receptor Agonist Responses
The mechanism of action of β2-adrenergic receptor agonists is complex and multifactorial, and a large number of gene polymorphisms may be expected to influence the efficacy of the drug. While cAMP is considered a major second messenger in the beneficial effects of this drug class – that is, smooth-muscle relaxation, several other mechanisms may be of relevance. Using a novel algorithm implemented in a family-based association test, Litonjua et al. screened the association of 844 genotyped SNPs in 111 candidate genes (42 involved in β2-adrenergic receptor signalling/regulation, 28 genes involved in glucocorticoid regulation, 41 genes from prior asthma association studies) in 209 children and their parents participating in the Childhood Asthma Management Program for their association with acute response to inhaled β2-adrenergic receptor agonists. This study identified the Arginase 1 (ARG1) SNP rs2781659 as being significantly associated with bronchodilator response (p = 0.047). In agreement, polymorphisms spanning ARG1 have been identified that influence patient response to salbutamol in a recent candidate gene study involving 221 asthma subjects. The ARG1 polymorphisms identified in both studies were in linkage disequilibrium (inherited together), suggesting a common causative mechanism involving potential transcriptional regulation as these polymorphisms were predominantly 5' to the gene. This alteration in transcription has now been confirmed in promoter-reporter studies, with the key ARG haplotype associated with improved bronchodilator response driving the highest level of ARG1 promoter activity. Interestingly, in the study by Vonk and colleagues, ARG2 SNPs were also associated with patient responses to salbutamol. Data from guinea pig models of allergic airway disease suggest that arginase enzymes deplete stores of L-arginine, a nitric oxide synthase substrate, in the airways leading to decreased nitric oxide levels, which normally acts to relax smooth muscle, resulting in airway hyper-responsiveness.
Recently, GSNOR SNP (rs1154400, promoter region) was associated with a decreased response to salbutamol in 107 African–American children. Within the same study, a post-hoc multilocus analysis identified that a combination of rs1154400 with ADRB2 Arg16Gly, Gly27Glu and the carbamoyl phosphate synthetase-1 (CPS1) SNP rs2230739 gave a 70% predictive value for lack of response to therapy. This implies that pharmacogenetic regulation of β2-adrenergic receptor agonist therapy may depend on several loci acting together via gene–gene interactions. In confirmation, four out of five SNPs tested within GSNOR were associated with asthma patient responses to salbutamol in 168 Puerto Rican asthma patients. These SNPs were also associated with asthma susceptibility and the key risk haplotype was associated with increased transcriptional activity based on promoter-reporter studies.GSNOR is an alcohol dehydrogenase that breaks down S-nitrosoglutathione, an endogenous bronchodilator. In addition, S-nitrosoglutathione regulates nitrosylation of proteins leading to alterations in function, including G protein-coupled receptor kinase 2, which phosphorylates and desensitises the β2-adrenergic receptor.
The identification of those patients at risk from potential adverse effects of β2-adrenergic receptor agonists remains a critical clinical question, as does the targeting of this class of drug to those patients most likely to gain benefit. While there has been clear progress with respect to study design for example, examining haplotypes instead of genotypes in isolation and adequately powered studies using thousands of individuals – there is still a need for large prospective studies of asthma patients with matched phenotypes and carefully controlled covariates including environmental influences. Similarly, these studies would benefit from GWA approaches and the identification of gene–gene interactions.
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