Genome-wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up

Abstract

RATIONALE: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent, and may depend on genetic factors. OBJECTIVES: To identify gene-environment interaction effects on childhood asthma using genome-wide single nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. METHODS: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctor's diagnosis of asthma up to 8 years in three European birth cohorts (n=1,534) with look-up for interaction in two separate North American cohorts, CHS and CAPPS/SAGE (n=1,602 and 186 subjects, respectively). We assessed eQTL effects in human lung specimens and blood, as well as associations between air pollution exposure, methylation and transcriptomic patterns. MEASUREMENTS AND MAIN RESULTS: In the European cohorts, 186 SNPs had an interaction p-value<1x10(-4) and look-up evaluation of these disclosed eight SNPs in four loci with interaction p<0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within ADCY2 showed same direction of interaction effect, and were found to influence ADCY2 gene expression in peripheral blood (p=4.50x10(-4)). One other SNP with p<0.05 for interaction in CHS, rs686237, strongly influenced B4GALT5 expression in lung tissue (p=1.18x10(-17)). Air pollution exposure was associated with differential DLG2 methylation and expression. CONCLUSION: Our results indicate that gene-environment interactions are important for asthma development and provide supportive evidence for interaction with air pollution for ADCY2, B4GALT5 and DLG2.