Exploring the Role of B-Cell Biotherapy in Myasthenia Gravis from a Genetic Perspective: A Mendelian Randomization...

Myasthenia gravis (MG) is an autoimmune disease caused by dysfunction at the neuromuscular junction. Current studies on MG are increasingly focusing on the involvement of B cell immunophenotypes in the development of the disease. Nonetheless, the specific correlation between B cells and MG still needs to be fully clarified. From published GWAS studies, we gathered summary results on B cell immunophenotypes and MG. We performed a Two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between B cells and MG. The primary estimation was done by using IVW and the Wald ratio. To assess pleiotropy and heterogeneity, a range of tests were utilized, including the Cochran Q test, MR-Egger intercept analysis, and the MR-PRESSO test. Next, we explored the potential for a reverse connection between B cells and MG using reverse MR analysis. Subsequently, in order to control for any potential confounding variables among the B cells, we carried out a multivariable MR analysis. Finally, we conducted co-localization analysis to examine the correlation between B cells and MG. Additionally, we repeated the above analysis process for two different MG subtypes. A total of 15 B cells were found to be significantly associated with MG, 7 B cells showed significant association with Early-onset MG, and 13 B cells showed significant association with Late-onset MG, as identified by MR analysis. We verified the reliability of the results by examining heterogeneity or pleiotropy. The Reverse MR analysis showed that there is bidirectional causality between 4 B cells and Early-onset MG, as well as between 2 B cells and Late-onset MG. To prevent confusion among B cells, we utilized multivariable MR analysis and identified that only 7 B cell immunophenotypes had independent effects on MG, while 4 B cell immunophenotypes had independent effects on Late-onset MG. None of the B cells had independent effects on Early-onset MG. Through colocalization analysis, it was found that two B-cell variants (rs75787009, rs354026) were associated with MG, along with two variants (rs138791329, rs11882257) were linked to Late-onset MG. Our results indicate a connection between B cells and the risk of MG, underscoring the possibility of using B-cell depletion therapy as a treatment option for MG patients based on genetic factors. Nevertheless, further research is needed to explore the specific mechanisms involved in this association.