Objective  To explore the causal relationship between immune cell phenotypes and the risk of developing gestational diabetes mellitus (GDM) by using Mendelian randomization (MR).

Methods  Using genome-wide association study data from European populations, we extracted 731 immune cell traits as instrumental variables, and obtained GDM summary statistics from the Finnish database (FinnGen). The inverse-variance weighted (IVW) method served as the primary estimator, supplemented by the weighted median, MR-Egger regression, simple mode, and weighted mode to evaluate the causal relationship between immune cell phenotypes and GDM, with additional tests for heterogeneity, horizontal pleiotropy, and sensitivity analyses. Reverse MR was further conducted to assess the potential causal impact of GDM on immune phenotypes.

Results  A total of 40 immune phenotypes showed potential causal associations with GDM risk. After false discovery rate correction (FDR<0.05), two phenotypes remained significant: HLA DR on CD33- HLA DR+ [OR=1.107, 95%CI (1.050, 1.166)] and HLA DR on DC [OR=1.098, 95%CI (1.048, 1.150)]. Reverse MR revealed no significant causal impact of GDM on any of the 40 immune phenotypes (P>0.05).

Conclusion  Specific immune cell phenotypes (HLA DR on CD33- HLA DR+, HLA DR on DC) may be potential causal risk factors for the development of GDM and may provide targets for future risk prediction and immune intervention strategies.

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