BACKGROUND: The biological mechanisms by which cleaning products and disinfectants - an emerging risk factor - affect respiratory health remain incompletely evaluated. Studying genes by environment interactions (GxE) may help identify new genes related to adult-onset asthma. OBJECTIVES: To identify interactions between genetic polymorphisms of a large set of genes involved in the response to oxidative stress, and occupational exposures to low molecular weight (LMW) agents or irritants on adult-onset asthma. METHODS: Data came from three large European cohorts: EGEA, SAPALDIA, and ECRHS. A candidate pathway-based strategy identified 163 genes involved in response to oxidative stress and potentially related with exposures to LMW agents/irritants. Occupational exposures were evaluated using an asthma job-exposure matrix and job-specific questionnaires for cleaners and healthcare workers. Logistic regression models were used to detect GxE interactions, adjusted for age, sex and population ancestry in 2599 adults (Mean age: 47 years, 60% women, 36% exposed, 18% asthmatics). P-values were corrected for multiple comparisons. RESULTS: Ever exposure to LMW agents/irritants was associated with current adult-onset asthma (OR(95%CI)=1.28(1.04,1.58)). Eight SNP by exposure interactions at five loci were found at p<0.005: PLA2G4A (rs932476, chromosome 1), near PLA2R1 (rs2667026, chromosome 2), near RELA (rs931127, rs7949980, chromosome 11), PRKD1 (rs1958980, rs11847351, rs1958987, chromosome 14), and PRKCA (rs6504453, chromosome 17). Results were consistent across the three studies and after accounting for smoking. CONCLUSIONS: Using a pathway-based selection process, we identified novel genes potentially involved in the adult asthma in relation with occupational exposure. These genes play a role in the NF-kB pathway involved in inflammation.