Causal Relationship Between Fatty Acid Metabolism and Allergic Asthma: A Mendelian Randomization and Multi-Omics Study

Allergic asthma (AAS) arises from intricate gene-environment interactions, yet its pathophysiological mechanisms remain incompletely understood. This study employs a multi-omics approach to elucidate the regulatory role of metabolites in AAS pathogenesis, aiming to identify novel therapeutic targets and preventive strategies. We conducted bidirectional two-sample Mendelian randomization (MR) analysis on 1,400 serum metabolites, followed by co-localization analysis to validate shared genetic loci. Metabolic pathway enrichment focusing on rate-limiting enzymes was performed, complemented by protein-protein interaction (PPI) network construction. MR was systematically applied to assess the impact of 17 lifestyle factors on AAS-associated metabolites. Six metabolites including Carnitine C14 (OR = 2.660) and 3-hydroxyoleoylcarnitine (OR = 1.620) showed significant associations with AAS after false discovery rate (FDR) correction (FDR < 0.05). Co-localization analysis (PPH3 + PPH4 > 0.9) identified fatty acid metabolism as the central pathway, with ACACB demonstrating significant interaction with salbutamol's target ADRB3. Lifestyle modulation analysis revealed cereal intake suppressed Carnitine C14 metabolism (P = 0.007), while cheese (P = 0.029) and oily fish consumption (P = 0.015) regulated 3-hydroxyoleoylcarnitine levels. This multi-omics integration study pioneers in delineating fatty acid metabolic reprogramming as a central mechanism in AAS pathogenesis. The identified ACACB-ADRB3 axis presents a novel therapeutic target, while dietary modulations of metabolite profiles offer promising avenues for personalized prevention strategies, advancing precision medicine in asthma management.