Pharmacogenomics and Placebo Response in a Randomized Clinical Trial in Asthma.

Wang RS1, Croteau-Chonka DC1, Silverman EK1, Loscalzo J2, Weiss ST1, Hall KT3.

Author information

1: Channing Division of Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
2: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
3: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Abstract

Genetic variation may differentially modify drug and placebo treatment effects in randomized trials (RCTs). In asthma, although lung function and asthma control improvements are commonplace with placebo, pharmacogenomics of placebo versus drug response remains unexamined. In a GWAS of subjective and objective outcomes with placebo treatment in Childhood Asthma Management Program (CAMP) of nedocromil/budesonide versus placebo (N=604), effect estimates for lead 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 which contains a lung function expression quantitative trait locus (eQTL). The effect was attenuated with budesonide (Pinteraction =1.48E-07), but not nedocromil (Pinteraction =0.06). The lead FVC SNP, rs12930749 (β=-5.80; P=1.47E-06), mapped to KIAA0556, a locus genome-wide associated with respiratory diseases. The rs12930749 effect was attenuated with budesonide (Pinteraction =1.32E-02) and nedocromil (Pinteraction =1.09E-02). Pharmacogenomic analysis revealed differential effects with placebo and drug treatment that could potentially guide precision drug development in asthma.