An integrative genomics approach identifies new asthma pathways related to air pollution exposure

The evidence on traffic-related air pollution exposure (TRAP) and incident childhood asthma is inconsistent, and may depend on genetic factors. We aimed to identify mechanisms of childhood asthma using genome-wide SNP data and individual TRAP exposure, and to evaluate the effect of susceptibility SNPs and TRAP on DNA-methylation and gene expression. We used LUR models to estimate individual outdoor NO 2 levels at the birth address and performed a genome-wide interaction study for doctor9s diagnosis of asthma up to 8 years in three European birth cohorts with replication in two North American cohorts (n=3,322 subjects). The top GWIS and replicated SNPs were assessed for methQTL effects in peripheral blood cells and eQTL effects in human lung specimens. Short- and long-term TRAP associations with methylation patterns and TRAP-induced differential gene expression in blood cells were also assessed. The novel loci MAGI1 , B4GALT5 , MOCOS and DLG2 , and the previously lung disease linked locus ADCY2 showed strong evidence for interaction with TRAP (genome-wide significance or replication). The top replication SNP rs686237 was identified as an eQTL for B4GALT5 (p=1.18x10 -17 ) and affected TRAP-induced gene expression (p=0.03). Differential methylation following TRAP exposure was seen for DLG2 , ADCY2 , MAGI1 and MOCOS . Identified genes belong to the guanylate kinase, sphingolipid and calcium signaling pathways, suggesting involvement in asthma pathogenesis. Our results indicate that gene-environment interactions are important for asthma development and that functional genomics analyses in conjunction with environmental exposures may give valuable insights about pathophysiologic mechanisms.