Genetically Predicted t6A (a tRNA-Derived Adenosine Modification) and Risk of Bullous Pemphigoid: A Two-Sample Mendelian Randomization Study.

PURPOSE: Bullous pemphigoid (BP) is an autoimmune blistering disease linked to T-lymphocyte dysregulation. Adenosine deaminase (ADA) and adenosine metabolites modulate T-cell function, suggesting a potential role in BP pathogenesis. However, causal evidence from human genetic studies is lacking. This study aimed to investigate the potential causal associations of genetically predicted levels of ADA, ADA protein, and several adenosine metabolites with the risk of BP and its subtypes (mucous membrane pemphigoid [MMP] and other/unspecified pemphigoid [OUP]).

PATIENTS AND

METHODS

We conducted a two-sample Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies (GWAS). Genetic instruments for ADA levels, ADA protein levels, 5-methylthioadenosine, N1-methyladenosine, N6-carbamoylthreonyladenosine (t6A), and N6-succinyladenosine were selected. Outcome data for BP, MMP, and OUP were obtained from the FinnGen R12 release. The primary analysis used the inverse-variance weighted (IVW) method. Sensitivity analyses included MR-Egger, weighted median, weighted mode methods, Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis.

RESULTS

Genetically predicted higher t6A levels were significantly associated with a lower risk of BP (IVW OR: 0.37, 95% Confidence Interval [CI]: 0.21-0.66; P < 0.001; P_FDR < 0.001). This association was supported by the weighted median method (OR: 0.39, 95% CI: 0.18-0.86; P = 0.02). No significant evidence of heterogeneity or horizontal pleiotropy was found for this association. No causal associations were observed for other adenosine metabolites, ADA levels, or ADA protein levels with BP, MMP, or OUP after FDR correction.

CONCLUSION

This MR study suggests a potential causal association between higher t6A levels and reduced risk of bullous pemphigoid. Further research is warranted to elucidate the underlying mechanisms and potential therapeutic implications.