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

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Background 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. Methods 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 [FEV 1 ] % predicted) using weighted linear regression. Gene expression data from bronchial epithelial cells (n = 170) were used to assess cis-expression quantitative trait loci (eQTLs). Findings Higher PM 2.5 exposure was associated with lower FEV 1 % predicted (β per μg/m 3 = −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 OXSR 1 and PXDN were associated with reduced gene expression and worsened FEV 1 % 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 FEV 1 %. Interpretation 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. Funding Supported by NIH grants.

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