Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity

Abstract

Background: Gene by environment interaction (G × E) studies utilizing GWAS data are often underpowered after adjustment for multiple comparisons. Differential gene expression, in response to the exposure of interest, may capture the most biologically relevant genes at the genome-wide level.

Methods: We used differential genome-wide expression profiles from the Home Allergens and Asthma Birth cohort in response to Der f 1 allergen (sensitized vs. non-sensitized) to inform a G × E study of dust mite exposure and asthma severity. Polymorphisms in differentially expressed genes were identified in GWAS data from CAMP, a clinical trial in childhood asthmatics. Home dust mite allergen (< or ≥ 10µg/g dust) was assessed at baseline, and (≥ 1) severe asthma exacerbation (emergency room (ER) visit or hospitalization for asthma in the first trial year) served as the disease severity outcome. The Genetics of Asthma in Costa Rica (GACRS) study, and a Puerto Rico/Connecticut asthma cohortwere used for replication.

Results: IL-9, IL-5 and PRG2 expression was up-regulated in Der f 1 stimulated PBMCs from dust mite sensitized individuals (adj. p value <0.04). IL-9 polymorphisms (rs11741137, rs2069885, rs1859430) showed evidence for interaction with dust mite in CAMP (p=0.02 to 0.03), with replication in GACRS (p=0.04). Subjects with the dominant genotype for these IL-9 polymorphisms were more likely to report a severe asthma exacerbation if exposed to elevated dust mite.

Conclusions: Genome-wide differential gene expression in response to dust mite allergen identified IL-9, a biologically plausible gene target that may interact with environmental dust mite to increase severe asthma exacerbations in children.