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.

Figure 1.

Manhattan plot for GWAS of coughing/wheezing by self-report in the placebo treatment arm of CAMP. Results are plotted as minus log-transformed P-values from coughing/wheezing model controlled for age, sex and clinic site. Even numbered chromosomes are in grey and odd numbered chromosomes in black. The black line delineates SNPs that exceed the genome-wide significance threshold of P<1.0E-05.

Figure 2.

Change in coughing/wheezing frequency stratified by rs2392165 (BBS9) genotype in the A) placebo; B) budesonide; and C) nedocromil treatment arms. Baseline (BL) and end of treatment (EoT) coughing/wheezing stratified by rs2392165 genotype in the D) placebo; E) budesonide; and F) nedocromil treatment arms. Box plots denote the median (dark line) and interquartile ranges, circles represent outliers.

Figure 3.

Manhattan plot for GWAS of FVC in the placebo treatment arm of CAMP. Results are plotted as minus log-transformed P-values from the genotype association FVC model controlled for age, sex and clinic site. Even numbered chromosomes are in grey and odd numbered chromosomes in black. The black line delineates SNPs that exceed the genome-wide significance threshold of 1.0E-05.

Figure 4.

Change in FVC (% of predicted) stratified by rs12930749 (KIAA0556) genotype in the three CAMP treatment arms A) placebo; B) budesonide; and C) nedocromil treatment arms. Baseline (BL) and end of treatment (EoT) FVC stratified by rs12930749 KIAA0556 genotype in the D) placebo; E) budesonide; and F) nedocromil treatment arms. The mean is denoted by the dark black lines bisecting the boxes which represent the standard deviations; the range is indicated by the dashed lines with outliers as the circles. Box plots denote the median (dark line) and interquartile ranges, circles represent outliers.