PGx7612: Pharmacogenetic investigation of the association of the ADRB2 rare variant, Thr164Ile with severe asthma exacerbation

Trial description: Asthma exacerbations continue to be a major concern for both subjects and their healthcare providers. The discovery of a genetic marker that predicts those most at risk for asthma exacerbations could potentially be used to prevent, or reduce the incidence of, such exacerbations.Ortega et al., 2014 reported the first study suggesting a genetic association between a rare variant and acute exacerbations following long acting beta agonist (LABA) treatment (Lancet Respiratory Medicine 2014; 2:204-213). The hypothesis in their paper is that low frequency ADRB2 variants modulate therapeutic response to LABAs and contribute to rare, severe adverse events including hospitalization. Six rare variants, including the Thr164Ile variant, were genotyped in 1165 subjects with asthma. In this subset of subjects from the Collaborative Studies on the Genetics of Asthma and the Severe Asthma Research Program collections, 46% (6 of 13) of LABA treated non-Hispanic white subjects who carried the Thr164Ile (T allele) variant were hospitalized, compared to 16% (61 of 384) of subjects who did not carry the variant. In the same paper, Ortega et al, 2014 reported that they were unable to replicate the association with hospitalization in an independent set of 659 non-Hispanic white asthma subjects.In GlaxoSmithKline (GSK)-sponsored studies of asthma medications with genetic samples available at the time of the Ortega et al publication, there were not enough subjects who had been hospitalized for asthma exacerbations while receiving LABA-containing regimens in clinical trial samples to conduct a well-powered study of the hospitalization endpoint. Therefore, to investigate the possible association of this low frequency variant with an asthma exacerbation phenotype, the current analysis used a related phenotype, clinically significant asthma exacerbation which required oral corticosteroid (OCS) treatment and/or an unscheduled clinic visit, including hospitalization, as defined by the GSK-sponsored clinical study criteria.The primary objective is to determine if there is evidence for the association of ADRB2 Thr164Ile with clinically significant asthma exacerbation in non-Hispanic white (NHW) subjects treated with LABA.