Centre for Genomic Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Department of Obstetrics and Gynaecology, Fertility Clinic, Copenhagen University Hospital, Herlev, Denmark.
J Assist Reprod Genet. 2020 Nov;37(11):2883-2892. doi: 10.1007/s10815-020-01941-0. Epub 2020 Sep 18.
To investigate if rare gene variants in women with severe ovarian hyperstimulation syndrome (OHSS) provide clues to the mechanisms involved in the syndrome.
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.
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.
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.
探究患有严重卵巢过度刺激综合征（OHSS）的女性中罕见的基因变异是否为该综合征相关机制提供线索。
在一项前瞻性随机研究（Toftager 等人，2016 年）的参与者中，选择了 6 名患有严重 OHSS（Golan 分类 4 和 5 级）的低风险和 6 名高风险的女性，预测其有发生 OHSS 的风险。在同一队列中，选择了 6 名未出现 OHSS 迹象（Golan 分级 0）的匹配对照者。进行全外显子组测序。使用预定义的计算机 OHSS 基因面板进行分析，对变体进行过滤，并进行通路分析。
我们使用计算机基因面板未发现与 OHSS 发展有明显的单基因关联。OHSS 变异列表的通路分析显示，在低风险和高风险组发展为严重 OHSS 的高度富集的主要通路（p 值范围为 p<0.0001 至 p>9.8E-17）之间存在显著重叠，即“整合素连接激酶（ILK）信号通路”和“轴突导向信号通路”，这两个通路都与血管活性内皮生长因子（VEGF）和内皮功能有关。
具有两种不同风险特征的 OHSS 病例中的罕见变异使相同的信号通路富集，这些信号通路与 VEGF 和内皮功能有关。阐明机制以及潜在地确定高血管通透性的遗传易感性对未来针对 OHSS 的靶向治疗和预防非常重要；ILK 信号通路和轴突导向信号通路的潜在作用需要通过功能研究来验证。
