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

BACKGROUND

Type 1 diabetes mellitus (T1DM) is a chronic disease mediated by autoimmunity, with complex and not fully elucidated pathogenesis. Mendelian randomization (MR) utilizes genetic instrumental variables to minimize confounding and reverse causation; however, individual MR studies are often limited by sample size and result heterogeneity.

METHODS

Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, and other databases from 2014 to 2025, ultimately including 53 MR studies (covering 243 exposures). Random-effects models were used to pool effect sizes. Heterogeneity was quantified by Cochran's Q test and I2 statistic. Bias was further controlled using Egger's regression and leave-one-out sensitivity analysis.

RESULTS

This study integrated 53 MR studies (243 exposures) and identified key causal factors for T1DM.IL2RA (OR = 0.22, 95% CI: 0.17-0.27) and TYK2 (OR = 0.61, 95% CI: 0.54-0.69) showed significant protective effects, while IL6R (OR = 1.98, 95% CI: 1.48-2.65) was associated with increased risk. For metabolites, 3-phenylpropionic acid (OR = 0.90, 95% CI: 0.85-0.96) and cinnamoylglycine (OR = 0.89, 95% CI: 0.84-0.96) were protective, while trimethylamine N-oxide (TMAO; OR = 1.11, 95% CI: 1.02-1.20) increased risk. Among gut microbiota, Prevotella 9 (OR = 1.18, 95% CI: 1.08-1.30) was positively associated with risk, whereas Bifidobacterium (OR = 0.82, 95% CI: 0.71-0.95) showed a protective effect. Childhood obesity (OR = 1.32, 95% CI: 1.06-1.64) was also associated with increased T1DM risk. Overall heterogeneity was high (I2 = 78.3%).

CONCLUSION

This study systematically mapped the multi-omics causal risk landscape of T1DM, providing important evidence for precision prevention and targeted intervention. These findings suggest that targeting immune pathways (particularly IL2RA and TYK2) and modulating gut microbiota composition may represent promising strategies for T1DM prevention. Future research should emphasize cross-ethnic validation and life-stage-specific intervention strategies.