Pathway analysis of a genome-wide gene by air pollution interaction study in asthmatic children

Objectives: We aimed to investigate the role of genetics in the respiratory response of asthmatic children to air pollution, with a genome-wide level analysis of gene by nitrogen dioxide (NO₂) and carbon monoxide (CO) interaction on lung function and to identify biological pathways involved. Methods: We used a two-step method for fast linear mixed model computations for genome-wide association studies, exploring whether variants modify the longitudinal relationship between 4-month average pollution and post-bronchodilator FEV₁ in 522 Caucasian and 88 African-American asthmatic children. Top hits were confirmed with classic linear mixed-effect models. We used the improved gene set enrichment analysis for GWAS (i-GSEA4GWAS) to identify plausible pathways. Results: Two SNPs near the EPHA3 (rs13090972 and rs958144) and one in TXNDC8 (rs7041938) showed significant interactions with NO₂ in Caucasians but we did not replicate this locus in African-Americans. SNP–CO interactions did not reach genome-wide significance. The i-GSEA4GWAS showed a pathway linked to the HO-1/CO system to be associated with CO-related FEV₁ changes. For NO₂-related FEV₁ responses, we identified pathways involved in cellular adhesion, oxidative stress, inflammation, and metabolic responses. Conclusion: The host lung function response to long-term exposure to pollution is linked to genes involved in cellular adhesion, oxidative stress, inflammatory, and metabolic pathways.