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

J Expo Sci Environ Epidemiol. 2019 Jun;29(4):539-547. doi: 10.1038/s41370-019-0136-3. Epub 2019 Apr 26.


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.

Keywords: Air pollution; Asthma; Gene–environment interaction; Genome-wide; Lung function; Pathways..

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Air Pollutants / analysis
  • Air Pollutants / toxicity*
  • Asthma / physiopathology*
  • Carbon Monoxide / analysis
  • Child
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Lung / physiopathology
  • Male
  • Nitrogen Dioxide / analysis
  • Respiratory Function Tests


  • Air Pollutants
  • Carbon Monoxide
  • Nitrogen Dioxide