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 (NO) 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 FEV 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 NO 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 FEV changes. For NO-related FEV 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.