Background: Many potential occupational asthmagens and their co-exposure risks are underestimated. We conducted an exposome-wide association study (ExWAS) to systematically explore occupational chemical exposures and estimate their joint association with adult asthma and related multimorbidity. Methods: This cross-sectional study included 3148 adults in the Personalized Environment and Genes Study (PEGS), a North Carolina-based cohort with questionnaire-based health and exposure data. Standardized questionnaires investigated occupational exposure to 93 chemical agents across 18 groups and the use of personal protective equipment (PPE). Current adult asthma was defined as self-reported doctor-diagnosed asthma with an attack in the prior year. Respiratory multimorbidity was ascertained if asthma coexists with allergic rhinitis or chronic obstructive pulmonary disease. Logistic regression-based ExWAS analyzed associations for individual chemicals. Weighted standardized polyexposure scores (PXS) were developed for predefined known asthmagens (PXS known) and suspected or novel risk agents (PXS suspected or novel) selected from ExWAS results through a regularized selection procedure. Results: Approximately 9.7% of adults reported current asthma. In ExWAS, ever exposure to cleaning liquids, heavy metals, dust, and combustion emissions, was positively associated with asthma [adjusted odds ratio (aOR): 1.50-2.10; false discovery rate (FDR)< 0.05)], particularly when exposure occurred weekly or lasted over one year. The top five specific risk agents were talc, ammonia, bleach, silica, and carbon monoxide. PXS known (four agents) and PXS suspected or novel (six agents) showed positive associations with asthma and multimorbidity (aOR: 1.22-1.94 per 0.1 increment). Additionally, participants PPE had reduced odds of asthma and respiratory multimorbidity in relation to PXS suspected or novel ( P interaction< 0.05). Conclusion: We identified six suspected and novel chemical risk agents not yet recognized as occupational asthmagens by major classification systems. PXS can effectively summarize joint exposure effects on asthma and respiratory multimorbidity, supporting occupational risk assessment in clinical and public health settings.

Background: Pathway-based approaches may effectively dissect the polygenic architecture of complex diseases. We conducted a semi-explorative interaction study between genome-wide and pathway-specific polygenic risk scores (PRS) and occupational asthmagens (i.e., cleaning agents) on adult asthma. Methods: This study included 2615 adults from the Personalized Environment and Genes Study (PEGS) in North Carolina, with comprehensive questionnaire-based health and exposure data and whole genome sequencing data. Occupational exposure to any cleaning agent was assessed as ever exposure to ammonia, chlorine bleach, and carbon tetrachloride over 15 minutes per week in any job. Current adult asthma was defined as doctor-diagnosed asthma with an attack in the past year. We estimated genome-wide PRS and pathway-specific PRS of oxidative stress and type 2 immune responses. We used 1) logistic regression to analyze interactions between PRS and exposure, and 2) linear principal-component regression to examine gene-based interactions. Results: Current asthma prevalence was 9.56% (n=250). Occupational exposure to cleaning agents was associated with an increased asthma risk [adjusted odds ratio (aOR): 1.56-2.24]. Genome-wide PRS multiplicatively interacted with any cleaning agent or bleach ( P _interaction =0.029 or 0.039), while pathway-based PRS conferred asthma risk independently. Additive interactions between cleaning agents and high genetic risks (PRS>median splits) were observed, showing the highest excess asthma risk in individuals with both exposure and pathway-based risks. Notably, eight genes were identified to explain oxidative stress PRS-related interaction with cleaning agents on asthma ( P _interaction < 0.05/29 genes). Conclusion: Applying novel and statically powerful pathway-based PRS, we found cleaning agents synergistically interacted with genetic risks of asthma, advancing mechanistic insights for precision prevention and intervention in asthma.

Background: Various residential hazards have been associated with asthma risk, with socially disadvantaged neighborhoods disproportionately affected by environmental exposures. This study aimed to explore geospatial-based neighborhood hazards and estimate their mixture effect on adult asthma risk by social vulnerability index (SVI). Materials and Methods: This cross-sectional study included 7092 adults from a North Carolina-based cohort (2013-2022). Adult asthma was defined as self-reported an asthma diagnosis with recurrent attacks in adulthood. Exposure to 29 residential hazards was estimated using spatiotemporal models and hazard maps, including multiple air pollutants, volatile organic compound emissions, highway density, and proximity to pollutant sources. The census tract-based SVI was assigned to participants’ residences. Associations between specific hazards and asthma were examined using logistic regression in high and low SVI groups (stratified by median percentile), and joint effects of mixture exposure were analyzed using quantile g-computation. Results: Residential proximity to dry-cleaning solvent contamination was positively associated with asthma in the overall population. In the high SVI group, seven additional hazards—particularly air pollutants—were significantly linked to increased asthma odds (False discovery rate, FDR< 0.05). A quintile increase in the mixture exposure was associated with a 35% (95% CI: 6%, 73%) higher odds of asthma in the high SVI group, which was more pronounced than in the low SVI group ( P _{for difference} = 0.038). Key contributors included toluene, dry-cleaning sites, organic matter in PM _2.5 , and carbon monoxide, each accounting for over 10% of the mixture effect. Socioeconomic and housing/transportation-related vulnerabilities interacted with key hazards and mixture exposure on asthma (FDR _interaction < 0.05). Conclusion: Residents of high SVI neighborhoods are more vulnerable to environmental hazard-related asthma risks. Targeted interventions should prioritize communities with poor socioeconomic, housing, and transportation conditions to effectively mitigate these environmental health risks.