Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids

Abstract

Background: To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations.

Objective: We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs.

Methods: We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults).

Results: The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10(-8) (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10(-5)), rs2388639 (combined P = 8.56 × 10(-9)), and rs10044254 (combined P = 9.16 × 10(-8)) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants.

Conclusions: We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.

Keywords: Asthma; child; glucocorticoid; pharmacogenomics; polymorphism.

Fig 1

Changes in asthma symptom scores after ICS treatment in the 2 pediatric asthma populations (CAMP and CARE) genotyped for rs10044254 and stratified by genotype status. Subjects in the CAMP and CARE trials who carried 2 variant alleles showed increases in asthma symptom scores after ICS treatment, whereas subjects that were homozygous for the reference allele and heterozygous showed decreases. Data represent medians (IQRs), and small circles represent subjects who were outliers from the first and the third quartiles.

Fig 2

FBXL7 gene expression in response to dexamethasone stimulation in immortalized B cells of the CAMP subject stratified by rs10044254 genotype. Reference represents expression data of B cells from the subjects with the reference allele, and Variant indicates expression data of B cells from the subjects with the variant allele (allelic model). Data represent medians (IQRs), and small circles represent subjects who were outliers from the first and the third quartiles.