Pathway-based genetic susceptibility and cleaning agent exposures in adult asthma: A semi explorative G x E analysis in the Personalized Environment and Gene Study (PEGS)

BackgroundPathway-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. MethodsThis 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. ResultsCurrent 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). ConclusionApplying 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.