Protein Network Analysis of Whole Exome Sequencing of Severe Preeclampsia

Abstract

Preeclampsia is a hypertensive disorder of pregnancy, which complicates up to 15% of US deliveries. It is an idiopathic disorder associated with several different phenotypes. We sought to determine if the genetic architecture of preeclampsia can be described by clusters of patients with variants in genes in shared protein interaction networks. We performed a case-control study using whole exome sequencing on early onset preeclamptic mothers with severe clinical features and control mothers with uncomplicated pregnancies between 2016 and 2020. A total of 143 patients were enrolled, 61 women with early onset preeclampsia with severe features based on ACOG criteria, and 82 control women at term, matched for race and ethnicity. A network analysis and visualization tool, Proteinarium, was used to confirm there are clusters of patients with shared gene networks associated with severe preeclampsia. The majority of the sequenced patients appear in two significant clusters. We identified one case dominant and one control dominant cluster. Thirteen genes were unique to the case dominated cluster. Among these genes, LAMB2, PTK2, RAC1, QSOX1, FN1, and VCAM1 have known associations with the pathogenic mechanisms of preeclampsia. Using bioinformatic analysis, we were able to identify subsets of patients with shared protein interaction networks, thus confirming our hypothesis about the genetic architecture of preeclampsia.

Large-Scale Proteomics in Early Pregnancy and Hypertensive Disorders of Pregnancy

“…To the best of our knowledge, among the top 8 proteins in our prediction model, only QSOX1, a marker of cellular growth and extracellular matrix remodeling, has previously been reported as having a role in pregnancy. 26,27 In those studies, higher levels of QSOX1 were found to be associated with preeclampsia, yet here we found higher levels of QSOX1 to be associated with lower risk of HDP. This finding is not dissimilar to that of sFlt-1, which has been shown to be elevated in the setting of clinically evident preeclampsia but has an inverse association with the subsequent development of preeclampsia when assayed early in pregnancy.…”

Variant Graph Craft (VGC): A Comprehensive Tool for Analyzing Genetic Variation and Identifying Disease-Causing Variants

“…Demonstrating VGC's capabilities, we present an example using whole exome sequencing data from preeclamptic patients and term mothers. The dataset includes 143 samples: 61 early onset severe preeclamptic cases and 82 term mother controls [16]. Through VGC, we offer a detailed analysis of this dataset, emphasizing major trends, statistical findings, and key outcomes aligned with our research goals.…”

Bioinformatics identification and validation of maternal blood biomarkers and immune cell infiltration in preeclampsia: An observational study

“…Fibronectin 1 (FN1) is a glycoprotein that is involved in cell adhesion and cell spreading and is widely distributed in healthy membranes, vascular structures, and smooth muscle cell layers. [25][26][27] The plasma levels of FN1, which may be the best marker for vascular endothelial injury during PE, are increased in patients with PE. [28] Multiple studies have shown that FN1 is related to the pathogenesis of PE, and FN1 can be used as a potential marker in the diagnosis of PE.…”