Potential Drug Targets and Causal Plasma Proteins Related to Preeclampsia Identified by Mendelian Randomization.

Abstract

Background: Preeclampsia (PE) is a complication of pregnancy characterized by hypertension, with limited therapeutic options and variable treatment response. Identifying novel drug targets is urgently needed.

Method: We performed Mendelian randomization (MR) to explore potential drug targets for PE using data from the UK Biobank (nCase = 184, nControl = 361,010) and the FinnGen database (nCase = 7,377, nControl = 211,957). Genetic instruments for pQTLs were obtained from five proteomic studies. Bayesian colocalization analysis and summary-data-based MR (SMR) analysis were performed to assess the causal relationship between two related signals (protein levels and PE risk). We further conducted single-cell type expression analysis and phenome-wide MR. In addition, a protein-protein interaction network of key genes was constructed via the GeneMANIA website.

Results: At a significance level of p < 5 × 10^-8, MR analysis revealed seven protein-PE pairs. Gene prediction indicated that KDEL (Lys-Asp-Glu-Leu) Containing 2 and Keratin 18 (KRT18) were positively correlated with the risk of PE, whereas the other five proteins (Complement Factor B [CFB], FYN Proto-Oncogene [FYN], RAN Binding Protein 1 [RANBP1], Amphoterin-Induced Gene and ORF 1 [AMIGO1], and Arginase 2 [ARG2]) were negatively correlated. None of the five proteins had reverse causality. Bayesian colocalization analysis verified the positive correlation of CFB (coloc.coloc.susie PPH4 = 1) and KRT18 (coloc.coloc.abf PPH4 = 0.74) with PE. The genes encoding the proteins KRT18, FYN, ARG2, and RANBP1 were distributed in specific cell types within PE tissues from patients with PE. Moreover, the examination of single-cell localization provided insights into the extensive distribution of the KRT18 gene, which is highly expressed in the villous cytotrophoblast (VCT) and extravillous trophoblast (EVT) populations.

Conclusion: Our MR analysis suggested that the plasma proteins KRT18, FYN, RANBP1, AMIGO1, and ARG2 had causal effects on PE risk. These findings indicated that these five proteins might be promising druggable targets for PE and warrant further clinical therapy, especially KRT18.