Causal relationships between immunophenotypes, plasma metabolites, and temporomandibular disorders based on Mendelian randomization

While numerous studies have underscored the implication of immune cells and metabolites in temporomandibular disorders (TMD), conclusive evidence for causality remains elusive. Consequently, our aim is to explore the causal connections between immunophenotypes and plasma metabolites in relation to TMD employing a bidirectional Mendelian randomization (MR) approach. Summary statistics data on 731 immunophenotypes (n = 3757) and 1091 plasma metabolites (n = 8299) were obtained from comprehensive genome-wide association studies (GWAS), while TMD data (5668 cases and 205,355 controls) were acquired from the FinnGen Consortium. Bidirectional MR analyses and a two-step MR approach assessed causal relationships and potential intermediaries. Various corrections and sensitivity analyses were utilized to assess the robustness of the findings. Two immunophenotypes and seven metabolites were significantly associated with TMD risk. Specifically, Alpha-hydroxyisovalerate mediated the link between CD33 on CD33dim HLA DR + CD11b + and TMD (β = 0.034, P = 5.95 × 10^-5), while CD8 on NKT cells mediated the causal relationship between 5-acetylamino-6-formylamino-3-methyluracil levels and TMD (β = 0.069, P = 5.11 × 10^-5). Our findings revealed the causal relationships between immunophenotypes and plasma metabolites on TMD from a genetic perspective, potentially aiding in TMD prevention.