Genome-wide analysis of gene and air pollution interactions on COPD in the CLSA cohort

Ambient air pollution contributes to chronic obstructive pulmonary disease (COPD), but the genetic factors that may influence susceptibility remain poorly defined. We conducted a genome-wide interaction analysis to identify genetic markers that may modify the association between air pollution and COPD. We analyzed data from 16,839 Canadian Longitudinal Study of Aging participants, including spirometry, genome-wide genotype data (645,625 single-nucleotide polymorphisms [SNPs]), and air pollution exposure estimates. COPD was defined as a forced expiratory volume in 1 second to forced vital capacity ratio (FEV₁/FVC) below the lower limit of normal. Annual average concentrations of particulate matter (PM_2.5), nitrogen dioxide (NO₂), and ozone (O₃), representing multi-year exposure estimates (2012-2015), were assigned to participants' residential postal code. Logistic regression models with SNP-by-air-pollutant interaction terms were applied, with a significant interaction threshold set at p < 7.74 × 10^-8 after Bonferroni correction. Significant interactions were observed between PM_2.5 and rs3762953 in CEP72/TPPP (P_interaction = 4.82 × 10^-8) and rs72802672 in WFDC1 (P_interaction=5.62 × 10^-8). For NO₂, significant interactions were observed with rs2585043 near ADAMTSL3/SH3GL3 (P_interaction=4.01 × 10^-8), rs6809120 in ADAMTS9 (P_interaction=4.53 × 10^-8), rs6761941 near EPCAM-DT/CALM2 (P_interaction=5.12 × 10^-8), rs113083358 in DLG2 (P_interaction=6.44 × 10^-8), and rs17801230 near FASTKD2/CPO (P_interaction=4.69 × 10^-8). These loci map to genes involved in microtubule and ciliary function, extracellular matrix remodeling and protease regulation, airway inflammation and smooth muscle contractility, and mitochondrial function. These findings highlight genetic modification of the association between air pollution and COPD susceptibility in low-exposure settings and offer mechanistic insight without implying direct clinical application.