Associations of Circulating Metabolites with Childhood Allergy and Common Allergic Diseases: A Mendelian Randomization Study

Asthma and other allergic diseases, driven by immune dysregulation, pose a significant global health burden. While observational and experimental studies suggest a link between metabolites and allergies, causality remains unclear. Genome-wide association study (GWAS) data for childhood allergies (CA; ncase = 6110, controls = 406,07) and typical allergic conditions included asthma, hay fever and eczema (ncase = 180,129, controls = 180,709) were used. Data on exposures were extracted from 136,016 Europeans for 233 circulating biomarkers and from 8,000 participants for 1400 plasma metabolites. The primary universal Mendelian randomization (UVMR) analysis used inverse variance weighting (IVW) and three supplementary methods for causal assessment. Sensitivity analyses included Cochran’s Q test, MR-Egger intercept and MR-PRESSO to ensure robustness. Leave-one-out (LOO) analysis evaluated bias by sequentially removing SNPs. Bonferroni correction was applied, and significant metabolites underwent pathway enrichment analysis. We identified 24 metabolic pathways potentially involved in the biological mechanisms of typical allergic diseases and CA. MR analysis revealed 3 circulating biomarkers and 57 metabiotic traits potentially linked to CA, while 2 biomarkers and 56 metabolites were causally related to typical allergic diseases. After genetic correction, the ratio of omega-6 fatty acids to total fatty acids (IVW: <i>p</i> = 0.015, OR: 0.816, 95% CI: 0.693-0.961) and bilirubin (E, E) level (IVW: <i>p</i> = 8.23 × 10⁻⁴, OR: 1.097, 95% CI: 1.039-1.578) remained significantly associated with CA. The significant roles of valine, leucine and isoleucine biosynthesis (<i>p</i> = 1.7 × 10⁻³) and degradation (<i>p</i> = 0.041) in allergic diseases were also identified. This study identified genetically determined metabolites and pathways significantly associated with asthma and other allergic diseases, offering novel insights into their pathogenesis