Causal Risk Factors for Type 1 Diabetes in Mendelian Randomization Studies: A Systematic Review and Meta-Analysis

Area of Science:

• Genetics and immunology
• Metabolomics
• Microbiome research

Background:

• Type 1 diabetes mellitus (T1DM) is an autoimmune disease with complex, incompletely understood pathogenesis.
• Mendelian randomization (MR) is a method to infer causality using genetic variants, minimizing confounding and reverse causation.
• Individual MR studies often face limitations due to small sample sizes and heterogeneous results.

Purpose of the Study:

• To systematically identify causal risk factors for T1DM using a large-scale meta-analysis of Mendelian randomization studies.
• To map the multi-omics causal risk landscape of T1DM for precision prevention and targeted interventions.

Main Methods:

• Systematic literature search following PRISMA 2020 guidelines across major databases (PubMed, Web of Science) from 2014-2025.
• Inclusion of 53 MR studies encompassing 243 distinct exposures.
• Application of random-effects models for effect size pooling, with heterogeneity assessed by Cochran's Q test and I² statistic, and bias controlled via Egger's regression and leave-one-out analysis.

Main Results:

• Identified protective effects for IL2RA (OR=0.22) and TYK2 (OR=0.61), and increased risk for IL6R (OR=1.98).
• Metabolites 3-phenylpropionic acid (OR=0.90) and cinnamoylglycine (OR=0.89) showed protective effects, while trimethylamine N-oxide (TMAO; OR=1.11) increased risk.
• Gut microbiota analysis revealed Prevotella 9 (OR=1.18) associated with increased risk and Bifidobacterium (OR=0.82) with protective effects; childhood obesity (OR=1.32) also increased risk.

Conclusions:

• This meta-analysis provides a comprehensive overview of multi-omics causal factors for T1DM.
• Targeting immune pathways (IL2RA, TYK2) and modulating gut microbiota are promising T1DM prevention strategies.
• Future research should focus on cross-ethnic validation and life-stage-specific interventions.