GSE125460
Pre-eclampsia TAC-seq
The etiology of preeclampsia, a hypertensive disorder of human pregnancy, remains unknown. We  addressed fetal sex selection and the suggestive role of fetal HLA-G and related genes, regulating  maternal immune responses, in preeclampsia pathogenesis.  We assessed birth sex ratios, weights, and seasonality of preeclampsia among 1.79 million births  in Finland. We studied haplotypes of HLA-G 3' untranslated region (UTR), regulating HLA-G  expression, in 1000 Genomes series and in a preeclampsia cohort (n=1249). We quantified  placental (n=163) mRNA expression of 136 genes, studied HLA-G and IFNa protein expression by  immunohistochemistry, and measured maternal and fetal circulating IFNa levels by ELISA.  Population-level data showed loss of male fetuses as a characteristic of preeclampsia. As a  potential contributor to immune-mediated loss, we found balancing selection at HLA-G 3'UTR  modulating sex ratio, and association of HLA-G 3'UTR haplotypes with placental HLA-G expression.  HLA-G and its receptors were downregulated in preeclampsia placentas, and surprisingly,  interferon alpha-1 (IFNA1) was highly upregulated. IFNA1 and HLA-G distinguished preeclampsia  better than placental FLT1 expression. Fetal but not maternal circulating IFNa, produced by  trophoblasts, showed association with maternal hypertension and fetal growth restriction.  We uncover the link between placental HLA-G expression and human birth sex ratio. We propose  that preeclampsia shares, through reduced HLA-G mediated immunotolerance, the mechanism  needed to fight placental viral infections and malaria in evolution. IFNa upregulation in  preeclampsia placenta, together with its known actions upstream of inflammatory genes,  encourages testing IFNa inhibitors and especially the pregnancy-approved antimalarial  hydroxichloroquine in treatment of preeclampsia. Overall design: 163 samples in total in 5 libraries (SATU1, SATU2, SATU3, SATU4, SATU5). 169 targets in total including 162 biomarker genes (136 remaining after QC) and 7 ERCC RNA Spike-In controls.