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