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Childhood asthma is likely the result of gene-by-environment (G × E) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide G × E studies of dust mite allergen on asthma-related phenotypes.We sought to identify genetic variants whose effects on lung function in children with asthma are modified by the level of dust mite allergen exposure.A genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (Puerto Rico Genetics of Asthma and Lifestyle [PRGOAL]). Replication was attempted in 2 independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study.Single nucleotide polymorphism (SNP) rs117902240 showed a significant interaction effect on FEV1 with dust mite allergen level in PRGOAL (interactionP= 3.1 × 10−8), and replicated in the same direction in CAMP white children and CAMP Hispanic children (combined interactionP= .0065 for replication cohorts and 7.4 × 10−9 for all cohorts). Rs117902240 was positively associated with FEV1 in children exposed to low dust mite allergen levels, but negatively associated with FEV1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CCAAT/enhancer-binding protein beta, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV1/forced vital capacity replicated in the independent cohorts.Dust mite allergen exposure modifies the estimated effect of rs117902240 on FEV1 in children with asthma. Analysis of existing data suggests that this SNP may have transcription factor regulatory functions.