Potential causal relationships between metabolites, immunophenotypes, and uveitis disease: A Mediation Mendelian Randomization Study

Abstract

Abstract Background There is substantial evidence that immune cells play a role in the pathogenesis of uveitis. Establishing causal relationships is challenging due to confounding biasing mechanisms of reverse causation and residual relationships. Methods Instrumental variables for 731 immune phenotypes, 1091 blood metabolites, and 309 metabolite ratios were derived from genome-wide association studies (GWAS) meta-analyses. The Integrated Epidemiology Unit (IEU) provides data on uveitis disease. A two-way Mendelian randomization study was performed to determine the relationship between exposure and outcome. Results were examined for robustness, potential heterogeneity, and horizontal pleiotropy through sensitivity analyses. Results High levels of CD3 on CM CD4+ were causally associated with an increased risk of uveitis (OR of IVW, 1.084; 95% CI, 1.032-1.139). This effect was found to be mediated through lower levels of phosphate to cysteine ​​ratio metabolites. Phosphate to cysteine ratio explained 8.56% (95% CI 0.593%, 16.5%) of the total effect of immune cell traits on uveitis. Conclusions Our study supports phosphate to cysteine ​​ratio as a mediating biomarker of CD3 on CM CD4+ effects in uveitis.