Causal effects and metabolite mediation of immune cells in preterm birth: a Mendelian randomization study

Preterm birth poses significant risks to neonatal health. Although immune dysregulation has been implicated in its etiology, the causal roles of specific immune cell phenotypes and the potential mediating effects of metabolites remain unclear. This study applied Mendelian randomization (MR) to investigate causal relationships between immune cell phenotypes and preterm birth, and to assess whether plasma metabolites mediate these associations.

Two-sample and mediation MR analyses were performed using genetic variants from genome-wide association studies (GWAS) of immune cells and plasma metabolites. Causal estimates were primarily derived using inverse variance weighting (IVW), with sensitivity analyses conducted via MR-Egger, MR-PRESSO, and leave-one-out validation.

A total of 28 immune cell phenotypes and 47 metabolites were robustly associated with preterm birth (P < 0.05). Reverse MR analysis revealed no evidence of reverse causality for the identified immune phenotypes. Among these, CD28^- CD8^br AC exhibited the strongest association with increased preterm birth risk. Mediation analysis demonstrated that the effect of CD28^- CD8^br AC on preterm birth (total effect: 0.148; IVW OR [95% CI]: 1.160 [1.056-1.274], P = 0.002) was partially mediated by isoleucine levels (mediation proportion: 6.79%; P = 0.027) and the acetylcarnitine-to-propionylcarnitine (C2/C3) ratio (mediation proportion: 7.35%; P = 0.029). Sensitivity analyses confirmed the robustness of these findings.

This study establishes causal links between immune cell phenotypes, metabolites, and genetic susceptibility to preterm birth. Specifically, CD28^- CD8^br AC may elevate preterm birth risk through modulation of isoleucine and the C2/C3 ratio, providing novel insights into disease mechanisms and potential therapeutic targets.