Genetically Predicted IgG N-Glycosylation Traits and Risk of Pre-Eclampsia or Eclampsia: A Two-Sample and Multivariable Mendelian Randomization Study.

BACKGROUND

Maternal immunoglobulin G (IgG) has been implicated in placental and vascular dysfunction across pre-eclampsia and eclampsia. While clinical evidence supports the relevance of IgG-mediated immune regulation, whether specific IgG N-glycosylation traits-which critically regulate IgG concentration and effector function-are associated with the combined outcome of pre-eclampsia or eclampsia remains unclear.

METHODS

A two-sample Mendelian randomization (MR) study evaluated the causal relevance of 77 IgG N-glycosylation traits for the combined outcome of pre-eclampsia or eclampsia. Primary analysis utilized the inverse-variance weighted method, supported by robust outlier and sensitivity diagnostics. Multivariable MR (MVMR) was subsequently applied to adjust for body mass index, gestational diabetes, C-reactive protein, interleukin-6, and tumor necrosis factor-α.

RESULTS

Univariable MR identified nine IgG N-glycosylation traits nominally associated with pre-eclampsia or eclampsia: five risk-increasing (IGP6, IGP11, IGP22, IGP46, IGP51) and four risk-decreasing (IGP31, IGP48, IGP50, IGP58). Sensitivity analyses confirmed no residual heterogeneity or directional pleiotropy. In MVMR, IGP46, IGP48, and IGP58 retained nominal associations after adjustment for BMI, GDM, CRP, IL-6, and TNF-α, suggesting more stable covariate-adjusted associations among the suggestive UVMR signals. IGP46 was positively associated with pre-eclampsia or eclampsia, whereas IGP48 and IGP58 showed consistent inverse associations. Structural annotation indicated that these prioritized traits were mainly related to fucosylation and monogalactosylation of IgG glycans.

CONCLUSION

This study provides suggestive genetic evidence that specific IgG N-glycosylation traits, particularly those related to core fucosylation and monogalactosylation, may be involved in the biological architecture of pre-eclampsia or eclampsia. The findings are hypothesis-generating and require validation in pregnancy-specific glycomic cohorts and functional studies.