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

Area of Science:

• Immunogenetics
• Environmental Health
• Pediatric Asthma Research

Background:

• Genome-wide association studies (GWAS) for gene-environment interactions are often limited by statistical power after multiple comparison adjustments.
• Differential gene expression (DGE) analysis can identify biologically relevant genes associated with specific environmental exposures.
• DGE in response to allergens can refine gene selection for subsequent gene-environment interaction studies.

Purpose of the Study:

• To utilize DGE profiles in response to Der f 1 allergen to inform a gene-environment interaction study.
• To investigate the association between dust mite exposure and asthma severity in children.
• To identify specific genes and polymorphisms that may mediate the relationship between dust mite exposure and severe asthma exacerbations.

Main Methods:

• DGE analysis was performed on peripheral blood mononuclear cells (PBMCs) from a birth cohort exposed to Der f 1 allergen.
• Genome-wide association study (GWAS) data from the Childhood Asthma Management Program (CAMP) was used to identify polymorphisms in differentially expressed genes.
• Home dust mite allergen levels and severe asthma exacerbations were assessed in CAMP participants. Replication was performed in two independent cohorts.

Main Results:

• IL9, IL5, and proteoglycan 2 (PRG2) gene expression was significantly upregulated in Der f 1-stimulated PBMCs from sensitized individuals (adjusted P < .04).
• IL9 polymorphisms (rs11741137, rs2069885, rs1859430) showed significant interaction with dust mite exposure in the CAMP cohort (P = .02 to .03), replicated in another cohort (P = .04).
• Individuals with specific IL9 genotypes were more prone to severe asthma exacerbations when exposed to higher dust mite levels.

Conclusions:

• Genome-wide DGE analysis successfully identified IL9 as a biologically plausible gene candidate.
• IL9 gene variants may interact with environmental dust mite exposure to elevate the risk of severe asthma exacerbations in children.
• This study highlights the utility of DGE in identifying key genes for gene-environment interaction studies in asthma research.