Metabolite quantitative trait loci provide functional link between FADS2 and lung obstruction in asthmatics

Rationale: FADS2 encodes a crucial rate limiting enzyme within omega-3/6 fatty acid pathways, and has been linked to asthma. Metabolomics is ideally suited to explore the downstream implications of FADS2 variants on the asthmatic phenotype. Methods: Blood collected at recruitment in the Childhood Asthma Management Program was submitted for metabolomic and genome-wide profiling. Metabolite Quantitative Trait Loci (mQTL) analysis was used to identify metabolites associated with 72 SNPs in FADS2. Mediation analysis was conducted to determine if the genetic burden of airway obstruction was mediated through alterations in these metabolites. Results: 495 asthmatic children, including 59 with airway obstruction (%predicted FEV1/FVC Conclusions: We leveraged integrative-omic data to demonstrate mQTLs near FADS2 may drive differential abundance of key inflammatory metabolites influencing asthma. The balance of omega-3/6 fatty acid conversion regulated by FADS2 is crucial for the resolution of inflammation and dampening of airway hyper-responsiveness. However, FADS2 likely exerts its influence through other metabolomic pathways.