Predictive genetic profiles for β-agonist therapy in asthma. A future under construction.

The goal of pharmacogenetic research is to determine the effects of genetic variation on the response of a phenotype to a pharmacologic agent. Pharmacogenetics has the potential to identify genetic biomarkers that can be used to stratify individuals for personalized therapies and, thus, place the individual at the center of therapeutic management decisions for precision medicine. Personalized medicine has a potential role in the treatment of asthma as a result of high interindividual variability in therapeutic responsiveness to the different classes of therapy for asthma. Among airways diseases, genetic studies have been successful in the development of personalized therapies for cystic fibrosis in individuals with specific rare coding variants in CFTR, yet no genetic variant has been successfully translated to the treatment of asthma (1). Pharmacogenetic studies addressing inhaled b2-adrenergic receptor agonist (b-agonist) response in asthma are unique among the different classes of pharmacologic therapies used to treat asthma, in that these studies address a controversy dating back to the 1960s. Epidemiologic studies identified an increased risk for asthma-related death during treatment with two less-selective inhaled short-acting b-agonists (SABAs) during mortality epidemics through the 1960s and 1970s, which resolved after the withdrawal of these drugs (2, 3). More recently, two large surveillance studies, including the Salmeterol Multicenter Asthma Research Trial, have shown a small increase in life-threatening asthma exacerbations and death during treatment with the longacting b-agonist (LABA) salmeterol (4). Despite clinical trial and meta-analytical evidence demonstrating the efficacy and safety of LABA when used in combination with an inhaled glucocorticoid, these safety concerns resulted in a boxed warning from the US Food and Drug Administration and a mandatory LABA safety study that is currently enrolling 46,800 patients with asthma (5). Identification of subgroups at risk for adverse responses to b-agonists is critical to understanding the mechanisms that underlie LABA safety and the development of biomarkers for personalized therapies. Genetic studies for b-agonist response in asthma have included biologic candidate genes in the b2-adrenergic receptor and nitric oxide biosynthetic pathways. Most studies have focused on the gene encoding the b2-adrenergic receptor (ADRB2), which has common coding variants, GlyArg and GlnGlu, with functional effects in vitro (6). GlyArg was associated with acute bronchodilation in response to albuterol and long-term response to regular albuterol treatment; however, this locus did not alter responses to LABA therapy in a number of genetic studies, including two genotype-stratified clinical trials (7–10). In a recent study, two rare ADRB2 variants were associated with hospitalization during LABA therapy, suggesting a role for rare variants in determining adverse responses (11). High-throughput whole-genome genotyping has recently provided an opportunity for unbiased genome-wide association studies (GWAS), which have discovered novel pharmacogenetic loci. The first GWAS for acute SABA bronchodilation identified a locus in spermatogenesis-associated serine-rich 2–like gene (SPATS2L) in non-Hispanic whites from six clinical trial cohorts and the National Heart, Lung, and Blood Institute Severe Asthma Research Program. MicroRNA knockdown of SPATS2L in human airway smooth muscle cells resulted in increased expression of the b2-adrenergic receptor (12). Two recent GWAS have identified additional novel loci associated with SABA bronchodilation, one of which used GWAS and admixture mapping to identify rare variants (allele frequency, ,0.05) in solute carrier genes (13, 14). Although some of the common variants identified in these GWAS were replicated in independent cohorts, none met the stringent threshold of genome-wide significance. In this issue of the Journal, Israel and colleagues (pp. 530–537) performed a GWAS of the degree of FEV1 bronchodilation after two or more inhalations of albuterol in 724 non-Hispanic white patients with asthma from the SHARE-Asthma Resource Project, which identified and replicated associations with four loci adjacent to the ankyrin repeat and SOCS (suppressor of cytokine signaling) box– containing 3 gene (ASB3) (15). A meta-analysis of the discovery and replication cohorts identified stronger associations for these single nucleotide polymorphisms (SNPs); thus, this GWAS was the first to report associations reaching genome-wide significance for b-agonist response in asthma. Israel and colleagues also identified plausible relationships between ASB3 and biologic pathways that regulate smooth muscle proliferation and b2-adrenergic receptor signaling, using bioinformatics database analyses to provide supporting biologic evidence for ASB3 as a pharmacogenetic locus. Are the variants identified by Israel and colleagues ideal genetic biomarkers for stratified, personalized treatment in an individual patient with asthma? The data presented are suggestive; however, more information is needed. The four SNPs identified in this GWAS were located approximately 1 million bases away from ASB3 and are likely surrogate-tagging SNPs for another causative variant. More detailed genotyping or DNA sequencing of the genomic region encompassing the regulatory and coding regions containing the SNPs identified in this GWAS and ASB3 will be necessary. In addition, the role of gene variation in ASB3 in the regulation of smooth muscle proliferation and b2-adrenergic receptor-mediated smooth muscle relaxation must be confirmed with in vitro functional studies. Could this novel pharmacogenetic locus for acute SABA bronchodilation alter responses to long-term, regular b-agonist treatment? The GlyArg locus in ADRB2 demonstrated contradictory effects on lung function response during acute bronchodilation versus long-term regular SABA therapy (7, 10). Furthermore, GlyArg genotype was not associated with clinical responsiveness to regular LABA therapy in multiple pharmacogenetic studies (8, 9). Therefore, the ASB3 locus should be evaluated in LABA-treated clinical trial cohorts. An important caveat is that although asthma management guidelines recommend that SABA therapy only be used as a rescue therapy, regular SABA treatment is still used in many areas of the world where asthma controller therapies are not readily available. Thus, the ASB3 locus could identify a subgroup of patients with asthma in whom regular SABA use is effective. It is also important to note that the clinical trial cohorts evaluated in this GWAS were treated EDITORIALS