Mendelian randomization analyses of known and suspected risk factors and biomarkers for myasthenia gravis overall and by subtypes.

ABSTRACT

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease that affects neuromuscular junction. The literature suggests the involvement of circulating cytokines (CK), gut microbiota (GM), and serum metabolites (SM) with MG. However, this research is limited to observational trials, and comprehensive causal relationship studies have not been conducted. Based on published datasets, this investigation employed Mendelian Randomization (MR) to analyze the known and suspected risk factors and biomarkers causal association of MG and its subtypes. METHODS: This research used two-sample MR and linkage disequilibrium score (LDSC) regression of multiple datasets to aggregate datasets acquired from the genome-wide association studies (GWAS) to assess the association of MG with 41-CK, 221-GM, and 486-SM. For sensitivity analysis and to validate the robustness of the acquired data, six methods were utilized, including MR-Egger regression, inverse variance weighting (IVW), weighted median, and MR-PRESSO. RESULTS: The MR method identified 20 factors significantly associated with MG, including 2 CKs, 6 GMs, and 9 SMs. Further analysis of the factors related to the two MG subtypes, early-onset MG (EOMG) and late-onset MG (LOMG), showed that EOMG had a high overlap with MG in the intestinal flora, while LOMG had a greater similarity in CKs and SMs. Furthermore, LDSC regression analysis indicated that Peptococcaceae, oxidized biliverdin, and Kynurenine had significant genetic correlations with general MG, whereas EOMG was highly correlated with Intestinibacter, while LOMG had significant genetic associations with Kynurenine and Glucose. CONCLUSION: This research furnishes evidence for the potential causal associations of various risk factors with MG and indicates a heterogeneous relationship between CKs, GMs, and SMs with MG subtypes.