Rare genetic variants suggest dysregulation of signaling pathways in low- and high-risk patients developing severe ovarian hyperstimulation syndrome

Abstract

Purpose To investigate if rare gene variants in women with severe ovarian hyperstimulation syndrome (OHSS) provide clues to the mechanisms involved in the syndrome. Methods Among participants in a prospective randomized study (Toftager et al. 2016), six women with predicted low and six women with predicted high risk of OHSS developing severe OHSS (grades 4 and 5, Golan classification) were selected. In the same cohort, six plus six matched controls developing no signs of OHSS (Golan grade 0) were selected. Whole-exome sequencing was performed. Analysis using a predefined in silico OHSS gene panel, variant filtering, and pathway analyses was done. Results We found no convincing monogenetic association with the development of OHSS using the in silico gene panel. Pathway analysis of OHSS variant lists showed substantial overlap in highly enriched top pathways (p value range p < 0.0001 and p > 9.8E-17) between the low-and high-risk group developing severe OHSS, i.e., "the integrin-linked kinase (ILK) signaling pathway" and the "axonal guidance signaling pathway," both being connected to vasoactive endothelial growth factor (VEGF) and endothelial function. Conclusion Rare variants in OHSS cases with two distinct risk profiles enrich the same signaling pathways linked to VEGF and endothelial function. Clarification of the mechanism as well as potentially defining genetic predisposition of the high vascular permeability is important for future targeted treatment and prevention of OHSS; the potential roles of ILK signaling and the axonal guidance signaling need to be validated by functional studies.

Severe Ovarian Hyperstimulation Syndrome in a Woman With Breast Cancer Under Letrozole Triggered With GnRH Agonist: A Case Report and Review of the Literature

“…The study of genetic variants of VEGF receptors could open new perspectives on the mechanisms involved in the syndrome. Borgwardt et al ( 32 ) evaluated the presence of genetic variants predisposing to the development of OHSS and found an association with the integrin-linked kinase (ILK) signaling pathway (2020). ILK signaling stimulated VEGF expression in tumor cells and VEGF-mediated endothelial activation ( 33 ).…”

Peripheral blood transcriptome analysis of patients with ovarian hyperstimulation syndrome through high-throughput sequencing

“…Blood parameters such as vascular permeability, serum estradiol, progesterone levels, and VGEF levels can be used to predict the incidence of OHSS to some extent during ovulation induction [7,21,22] . Because of improvements in high-throughput sequencing technology, a greater number of sequencing studies on samples obtained from patients with OHSS have been performed to study the mechanism of OHSS in detail [23,24] . Lin et al , for example, used follicular fluid from oocyte extraction for transcriptome sequencing to explain the underlying processes of OHSS occurrence and examine transcription variations in long-chain non-coding RNAs from high-risk patients with OHSS [17] .…”

Global Transcriptional Profiling of Granulosa Cells from Polycystic Ovary Syndrome Patients: Comparative Analyses of Patients with or without History of Ovarian Hyperstimulation Syndrome Reveals Distinct Biomarkers and Pathways

“…The pathway and gene network analyses revealed significant alterations in the PPAR, IL6, IL10, FOXO, JAK/STAT and NF-κB signaling pathways and potentially critical roles of IL33 , VEGF , INSR , FOS , TGf-β , LIFR , and immunoglobulin that may be relevant to the pathophysiology of OHSS [ 52 , 53 , 54 ]. Indeed, previous studies also reported the involvement of the immune system, cytokines, and growth factors in the pathogenesis of OHSS [ 52 , 53 , 55 , 56 ].…”

“…Indeed, previous studies also reported the involvement of the immune system, cytokines, and growth factors in the pathogenesis of OHSS [ 52 , 53 , 55 , 56 ]. For example, VEGF was implicated as having a significant role in the development of OHSS [ 26 , 52 , 54 , 57 ]. IL33 acts as both an extracellular cytokine and an intracellular nuclear factor with transcriptional regulatory properties [ 58 ].…”

“…This was, indeed, achieved after several years of sample collection. For whole-genome studies of such rare human diseases, including PCOS/OHSS, this number is considered a reasonable number to be able to identify differentially expressed genes (DEGs) for discovery-related investigations [ 6 , 54 , 65 ]. In addition, we used a stringent cutoff for selecting the DEGs; a p -value (of less than 0.01) as well as the fold change criteria.…”