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.

Genome-wide interaction study of dust mite allergen on lung function in children with asthma

“…Previous G×E studies of candidate genes have reported that dust mite exposure modifies the effects of IL-9 and IL-10 polymorphisms on asthma exacerbations 15,18 , TGF-β1 variants on asthma severity 16 , or purinergic receptor gene P2RY12 haplotypes on lung function 17 . Our results extend current knowledge on the topic by identifying novel polymorphisms using a genome-wide approach.…”

“…Gene-by-allergen interactions have been reported for dust mite and several candidate genes for asthma, including IL10 15 , TGFB1 16 , or the purinergic receptor P2RY12 17 . More recently, a study using genome-wide expression in vitro responses to dust mite allergen reported that IL9 may interact with environmental dust mite allergen and increase severe asthma exacerbations 18 . In the present study, we performed a genome-wide study interaction study (GWIS) of house dust mite allergen ( Dermatophagoides pteronyssinus ) level on lung function in Puerto Rican children with asthma, with replication studies in two independent cohorts of children with asthma.…”

Gene–Environment Interactions—What Can These Tell Us about the Relationship between Asthma and Allergy?

“…One of these studies was not able to replicate findings in all the populations studied [(28), p. 885–92.e2]. The final exposure considered in gene–environment interactions for asthma in this review is exposure to a farming environment.…”

Personalized management of asthma exacerbations: lessons from genetic studies

“…Higher levels of dust mite allergen exposure led to SNP-specific effects of increased AHR for the exonic SNP rs1800470:G>A and increased asthma exacerbations for the promoter SNP rs2241712:C>T[27]. Similarly, elevated dust mite exposure has been also shown to increase the odds of a severe asthma exacerbation by three to four-fold in US Caucasian and Costa Rican children who have the IL-9 polymorphism rs11741137:C>T or rs2069885:G>A[52]. Of note, the polymorphisms rs11741137:C>T and rs2069885:G>A in IL-9 are in linkage disequilibrium (r 2 = 0.99) and measure the same effect.…”