The causal relationship between circulating metabolites and gestational hypertension, pre-eclampsia, eclampsia: A bidirectional two-sample Mendelian randomization study.

Objective: Gestational hypertension, pre-eclampsia, and eclampsia pose significant risks to maternal and fetal health, yet their underlying causes remain unclear. This study investigates the associations between 233 metabolites and these conditions.

Methods: We analyzed data from the Genome-Wide Association Studies (GWAS) database for gestational hypertension, pre-eclampsia, and eclampsia. The bidirectional two-sample MR analysis examined causal relationships using inverse variance weighting as the primary method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses assessed robustness, heterogeneity, and horizontal pleiotropy.

Results: In the forward Mendelian randomization analysis, a reduction in citrate levels (OR = 0.906, 95% CI = 0.829-0.990, p = .029) is associated with an increased risk of gestational hypertension. The ratio of conjugated linoleic acid to total fatty acids (OR = 1.172, 95% CI = 1.026-1.339, p = .019) is associated with an increased risk of gestational hypertension. The ratio of conjugated linoleic acid to total fatty acids (OR = 1.288, 95% CI = 1.064-1.560, p = .009) is associated with an increased risk of preeclampsia and eclampsia. The phospholipids to total lipids ratio in large HDL (OR = 1.227, 95% CI = 1.120-1.344, p = 9.91 × 10^-6) is associated with an increased risk of preeclampsia and eclampsia. The total cholesterol to total lipids ratio in chylomicrons and extremely large VLDL (OR = 0.884, 95% CI = 0.789-0.990, p = .033) is associated with an increased risk of preeclampsia and eclampsia. In the reverse Mendelian randomization analysis, the occurrence of gestational hypertension is associated with a reduction in Cholesteryl esters to total lipids ratio in very large VLDL (OR = 0.987, 95% CI = 0.975-0.999, p = .044). The occurrence of preeclampsia and eclampsia is associated with a reduction in total choline levels (OR = 0.989, 95% CI = 0.979-0.998, p = .029), and with a reduction in total phosphoglycerides levels (OR = 0.988, 95% CI = 0.978-0.997, p = .012). Sensitivity analysis did not detect significant heterogeneity or pleiotropy.

Conclusion: This research elucidates the causal links between specific metabolites and gestational hypertension, pre-eclampsia, and eclampsia, potentially informing new clinical approaches for diagnosis and treatment.