Pharmacogenomics and Placebo Response in a Randomized Clinical Trial in Asthma

Abstract

Genetic variation may differentially modify drug and placebo treatment effects in randomized clinical trials. In asthma, although lung function and asthma control improvements are commonplace with placebo, pharmacogenomics of placebo vs. drug response remains unexamined. In a genomewide association study of subjective and objective outcomes with placebo treatment in Childhood Asthma Management Program of nedocromil/budesonide vs. placebo (N = 604), effect estimates for lead single nucleotide polymorphisms (SNPs) were compared across arms. The coughing/wheezing lead SNP, rs2392165 (β = 0.94; P = 1.10E-07) mapped to BBS9, a gene implicated in lung development that contains a lung function expression quantitative trait locus. The effect was attenuated with budesonide (P_interaction = 1.48E-07), but not nedocromil (P_interaction = 0.06). The lead forced vital capacity SNP, rs12930749 (β = -5.80; P = 1.47E-06), mapped to KIAA0556, a locus genomewide associated with respiratory diseases. The rs12930749 effect was attenuated with budesonide (P_interaction = 1.32E-02) and nedocromil (P_interaction = 1.09E-02). Pharmacogenomic analysis revealed differential effects with placebo and drug treatment that could potentially guide precision drug development in asthma.