Herpesvirus entry mediator on T cells as a protective factor for myasthenia gravis: A Mendelian randomization study

Abstract

Background and objectives: Myasthenia gravis (MG) is a T cell-driven, autoantibody-mediated disorder affecting transmission in neuromuscular junctions. The associations between the peripheral T cells and MG have been extensively studied. However, they are mainly of observational nature, thus limiting our understanding of the effect of inflammatory biomarkers on MG risk. With large data sets now available, we used Mendelian randomization (MR) analysis to investigate whether the biomarkers on T cells are causally associated with MG and further validate the relationships.

Methods: We performed a two-sample MR analysis using genetic data from one genome-wide association study (GWAS) for 210 extensive T-cell traits in 3,757 general population individuals and the largest GWAS for MG currently available (1,873 patients versus 36,370 age/gender-matched controls) from US and Italy. Then the biomarkers of interest were validated separately in two GWASs for MG in FIN biobank (232 patients versus 217,056 controls) and UK biobank (152 patients versus 386,631 controls).

Results: In the first analysis, three T-cell traits were identified to be causally protective for MG risk: 1) CD8 on terminally differentiated CD8⁺ T cells (OR [95% CI] = 0.71 [0.59, 0.86], P = 5.62e-04, adjusted P =2.81e-02); 2) CD4⁺ regulatory T proportion in T cells (OR [95% CI] = 0.44 [0.26, 0.72], P = 1.30e-03, adjusted P =2.81e-02); 3) HVEM expression on total T cells (OR [95% CI] = 0.67 [0.52, 0.86], P = 1.61e-03, adjusted P =2.81e-02) and other eight T-cell subtypes (e.g., naïve CD4+ T cells). In particular, HVEM is a novel immune checkpoint on T cells that has never been linked to MG before. The SNPs on the TNFRSF14 per se further support a more direct link between the HVEM and MG. The validation analysis replicated these results in both FIN and UK biobanks. Both datasets showed a concordant protective trend supporting the findings, albeit not significant.

Conclusion: This study highlighted the role of HVEM on T cells as a novel molecular-modified factor for MG risk and validated the causality between T cells and MG. These findings may advance our understanding of MG's immunopathology and facilitate the future development of predictive disease-relevant biomarkers.

Keywords: GWAS; HVEM; Mendelian randomization; T cell; myasthenia gravis.

Figure 1

The workflow of instrumental SNP selection and Mendelian randomization (MR) analysis.

Figure 2

MR result in primary analysis (US and Italian patients). SNP N, number of SNP. The top 12 ranked T-cell traits by P value show protective effect on MG risk after false discovery rate (FDR) adjustment.

Figure 3

MR result in secondary analysis (FIN and UK Biobanks). Before P value adjustment, only the first ranked exposure “CD8 on terminally differentiated CD8⁺ T cell” barely showed significance in the UK biobank dataset. However, after FDR adjustment, no exposures reach significance, but the tendencies of which are basically in accordance with the primary analysis (as protective factors). This can be explained by the low powers in all analysis due to paucity in patients.