Druggable targets and immunological mechanisms for type 1 diabetes treatment: Genetic evidence from multi-omics...

Type 1 diabetes mellitus (T1DM) frequently leads to severe complications, which can result in patient mortality or disability, imposing significant economic and psychological burdens on both individuals and society. In recent years, the incidence and prevalence of T1DM have been steadily increasing. However, the pathogenesis of the disease remains not fully understood; preventive measures are still lacking, and current treatments do not address the underlying causes. Mendelian randomization (MR) has recently gained widespread application in the identification of novel therapeutic targets.

First, QTL from three discovery datasets, representing druggable targets, was used as instruments, and the MR was performed to test causal association with T1DM using large T1DM GWAS data. Subsequently, sensitivity analyses were conducted, including confounder exclusion, directional testing, Bayesian colocalization and Spearman correlation analysis, to ensure the robustness of the results. Additionally, we explored which among the 731 types of immune cells could potentially mediate the impact of candidate targets on T1DM and assessed potential side effects related to the candidate targets through phenome-wide association study (PheWAS). We also performed MR analysis to evaluate the impact of these targets on T1DM complications. Finally, effect estimates were integrated through meta-analysis.

A total of 11 potential druggable targets for T1DM were identified. Some of which may also play a role in modulating the development of T1DM complications. Moreover, myeloid cells (CD33dim HLA-DR+ CD11b-) are likely mediators of the pathogenic effect of CTSH. Mediation analysis indicated that this cell type may potentially mediate the effect of CTSH on the pathogenesis of T1DM (OR = 1.014, 95% CI: 1.004-1.024, p = 0.008), with a mediation proportion of 8.3%. Phenome-Wide Association Studies (PheWAS) indicated that NAGA, NAAA, ITIH3 and CTSH may influence additional phenotypes.

This study used a Mendelian randomization approach to provide genetic evidence, providing insights and direction for the development of preventive and therapeutic drugs for T1DM.