PGx7648: Exploratory PGx analysis of ADRB2 Thr164Ile on risk of severe asthma exacerbation in study 201722

Trial description: Asthma exacerbations continue to be a major concern for both patients and their healthcare providers. The discovery of a genetic variant that predicts those most at risk for asthma exacerbations could potentially be used to prevent, or reduce the incidence of, such exacerbations.The hypothesis in Ortega et al. [2014] is that rare ADRB2 variants modulate therapeutic response to long-acting beta agonists (LABAs) and contribute to rare, severe adverse events including those resulting in hospitalization. They reported that 46% (6 of 13) of LABA-treated non-Hispanic white (NHW) subjects who carried the Thr164Ile (T allele) variant had asthma-related hospitalization events, compared to only 16% (61 of 384) of non-carriers. Although the same paper reported a failure to replicate the association with asthma-related hospitalizations, no inference can be made from this statement, because the replication dataset was grossly underpowered: Of 659 NHW asthma subjects in the replication dataset, only N=13 had asthma-related hospitalizations, compared with N=67 in the discovery dataset. Additional support for the discovery association includes significant association of the Thr164Ile variant with several measures of symptom control or severity in both the NHW discovery and replication datasets.In GlaxoSmithKline (GSK)-sponsored studies of asthma medications marketed prior to 2015 in subjects with mild to moderate asthma, the number of subjects who were hospitalized for asthma exacerbations while receiving LABA-containing regimens was insufficient to examine if the results of Ortega et al. [2014] with respect to the hospitalization endpoint could be replicated. However, study 201722, which recruited subjects who met criteria for severe asthma had hospitalization rates for exacerbation that were higher than among subjects from the other previously completed GSK asthma studies, presenting an opportunity to examine the findings of Ortega et al. [2014]. In addition to association with hospitalization, the association of the ADRB2 Thr164Ile variant with the asthma exacerbation rate was tested.Study 201722 was not designed explicitly for this pharmacogenetic analysis. The current analysis is based on information abstracted from medical records for the year prior to enrollment.The primary objective is to determine if there is evidence for the association of ADRB2 Thr164Ile with hospitalization caused by asthma exacerbation in NHW subjects treated with a LABA-containing regimen. The secondary objective is to determine if there is evidence for the association of ADRB2 Thr164Ile with asthma exacerbation rate in NHW subjects treated with LABA.