Negative Emotions Induce Urticaria by Regulating Metabolites: A Two-Step Mendelian Randomization Study

Introduction: Several studies have indicated a potential link between emotions and urticaria. However, the causal relationship between different emotions and urticaria and its subtypes, as well as whether circulating metabolites act as mediators, remains unclear. Methods: Instrumental variables for eight negative emotions, 1400 circulating metabolic factors, and urticaria were sourced from publicly available GWAS summary data. We used Mendelian randomization (MR) to explore the causal links between emotions, circulating metabolites, and urticaria, utilizing inverse variance weighting (IVW) as the main statistical approach. Result: The MR analysis results showed that nervous feelings (P=0.046; 95% CI:1.02–7.65) and worrier/anxious feelings (P=0.016; 95% CI:1.17–4.60) may be risk factors of urticaria. In addition, we found that 17 metabolites and three metabolite ratios increased the risk of urticaria, while 18 metabolites and two metabolite ratios were protective factors. Conclusion: The mediating MR analysis revealed that worrier/anxious feelings increase urticaria risk by decreasing mannose, mannonate, and glycosyl-N-(2-hydroxynervonoyl)-sphingosine (d18:1/24:1(2OH)) levels and by increasing the phosphate-to-mannose ratio and glucose-to-mannose ratio. However, the relationship between nervous feelings and urticaria is not mediated by metabolites. These findings provide new perspectives and potential strategies for the comprehensive prevention and treatment of urticaria through emotional and metabolic interventions.