A cross-sectional study of oxidative stress pathway genotypes and their interactions with environmental pollutant levels identifies associations with gene expression and lung function.

Abstract

Asthma is a heterogeneous disease influenced by genetic and environmental factors. Fine particulate matter (PM_2.5) exacerbates asthma, likely through oxidative stress pathways, but whether genetic variation modifies this effect remains unclear. We analysed data on 948 adults with asthma from the Severe Asthma Research Program (SARP), linking ZIP-code-level PM_2.5 exposure with whole-genome sequencing data. We tested 4337 single nucleotide polymorphisms (SNPs) in 120 oxidative stress pathway genes for gene-environment (GxE) interactions with PM_2.5 on lung function (forced expiratory volume in 1 s [FEV₁] % predicted) using weighted linear regression. Gene expression data from bronchial epithelial cells (n = 170) were used to assess cis-expression quantitative trait loci (eQTLs). Higher PM_2.5 exposure was associated with lower FEV₁% predicted (β per μg/m³ = -0.7, p = 0.01). We identified 20 SNPs across seven genes (OXSR1, PXDN, TPO, LRRK2, APP, MSRA, MSRB2) with significant GxE interactions after multiple-testing correction. Five SNPs were also eQTLs, linking PM_2.5-modified gene expression to lung function. Minor alleles in OXSR1 and PXDN were associated with reduced gene expression and worsened FEV₁% under high PM_2.5 exposure. Conversely, TPO variants were associated with higher baseline expression and lower lung function, but under increasing PM_2.5 exposure, minor allele carriers showed suppressed TPO expression and improved FEV₁%. This study identified 20 SNPs in oxidative stress pathway genes that modify the effect of PM_2.5 on lung function in asthma. These findings highlight the importance of integrating environmental context in genetic studies and suggest potential therapeutic targets for pollution-sensitive asthma phenotypes. Supported by NIH grants.