Bidirectional Mendelian Randomization Analysis Reveals Protective Effects of Bioavailable Testosterone Against Hypertensive Disorders of Pregnancy

Abstract Background and Objective Hypertensive disorders of pregnancy (HDP) substantially increase maternal and fetal morbidity and mortality. Although reduced circulating bioavailable testosterone (BT) has been observed in women with HDP, the causal relationship and underlying mechanisms remain unresolved. Based on previous clinical and experimental evidence, we hypothesized a potential causal relationship between BT levels and HDP, with subsequent analyses designed to explore the possible metabolic and anti-inflammatory pathways involved. Methods Summary statistics for BT and HDP were obtained from the IEU OpenGWAS database. A two-sample Mendelian randomization (MR) framework was implemented to evaluate causality, complemented by extensive sensitivity analyses to strengthen robustness. To explore potential mechanisms, expression quantitative trait loci (eQTL) integration, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein–protein interaction (PPI) network analyses were performed. Results MR analyses provided evidence of a protective causal effect of BT on HDP (IVW OR = 0.81, 95% CI: 0.68–0.97, P = 0.023), with no indication of reverse causality. Sensitivity tests consistently confirmed the reliability of these findings. Genes associated with BT-related SNPs were enriched in metabolic and immune pathways, notably the NOD-like receptor and IL-17 signaling pathways. Within the PPI network, NFKBIA emerged as a pivotal regulator of NF-κB signaling, thereby supporting a role for testosterone-mediated modulation of inflammation in HDP protection. Conclusion From a genetic standpoint, BT appears to act as a protective factor against HDP, potentially safeguarding cardiovascular function through interconnected metabolic and anti-inflammatory mechanisms.