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Reduced HSD17B1 expression in preeclampsia: integrated transcriptomic, summary Mendelian randomization, immune
Keng Ling1,2, Minping Hong3, Liqin Jin3
1Central Laboratory, Jiaxing Women & Children's Hospital, Wenzhou Medical University, Jiaxing, China.
Background:
17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) is a key placental steroidogenic enzyme that converts estrone to estradiol. Prior studies have suggested that reduced placental or circulating HSD17B1 is associated with preeclampsia (PE), but its position within the broader transcriptomic landscape and its relationship to immune changes remain incompletely characterized.
Methods:
Placental transcriptomic data from GSE75010 (77 controls and 80 PE placentas) were analyzed to identify differentially expressed genes (DEGs). Summary data-based Mendelian randomization (SMR) integrating eQTLGen cis-eQTL data with FinnGen preeclampsia summary statistics was then used to prioritize candidate genes. Immune cell infiltration was explored by CIBERSORT using the placental bulk transcriptomic matrix. Independent validation was performed in a clinical cohort comprising 96 women with PE and 96 normotensive pregnant controls by maternal plasma ELISA at 17-18 weeks of gestation and placental RT-qPCR at delivery.
Results:
DEG analysis identified 207 genes (152 upregulated and 55 downregulated) in PE placentas. HSD17B1 was the single overlapping candidate prioritized by both DEG and SMR analyses, and genetically predicted higher HSD17B1 expression showed an inverse association with PE risk under nominal SMR significance criteria. In the validation cohort, plasma HSD17B1 was lower in women with PE than in controls, and placental HSD17B1 mRNA was also significantly reduced. Exploratory immune deconvolution showed altered proportions of plasma cells, CD8 T cells, regulatory T cells, resting CD4 memory T cells, resting mast cells, eosinophils, and neutrophils in PE placentas; HSD17B1 expression correlated with several of these subsets.
Conclusions:
HSD17B1 is consistently downregulated in PE across public placental transcriptomic data and an independent validation cohort. When interpreted together with prior literature on miR-210/miR-518c, ESRRG signaling, and trophoblast differentiation, these findings support HSD17B1 as a biologically plausible PE-associated marker. However, the present study does not establish whether reduced HSD17B1 is a cause or a consequence of PE, and the immune findings should be regarded as exploratory.
