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.

中文翻译：

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罕见的遗传变异表明发生严重卵巢过度刺激综合征的低风险和高风险患者的信号通路失调。

目的

研究严重卵巢过度刺激综合征 (OHSS) 女性的罕见基因变异是否为该综合征所涉及的机制提供线索。

方法

在一项前瞻性随机研究（Toftager 等人，2016 年）的参与者中，选择了 6 名预测为 OHSS 低风险的女性和 6 名预测为高风险的 OHSS 女性（4 级和 5 级，Golan 分类）。在同一队列中，选择了 6 加 6 匹配的对照，没有出现 OHSS（戈兰 0 级）的迹象。进行了全外显子组测序。使用预定义的 in silico OHSS 基因面板进行分析、变体过滤和通路分析。

结果

我们使用计算机基因面板没有发现与 OHSS 的发展有令人信服的单基因关联。OHSS 变异列表的通路分析显示，在发展为严重 OHSS 的低风险和高风险组之间的高度富集的顶级通路（p值范围p < 0.0001 和p > 9.8E-17）存在大量重叠，即“整合素相关激酶(ILK) 信号通路”和“轴突引导信号通路”，两者都与血管活性内皮生长因子 (VEGF) 和内皮功能有关。

结论

具有两种不同风险特征的 OHSS 病例中的罕见变异丰富了与 VEGF 和内皮功能相关的相同信号通路。阐明机制以及潜在定义高血管通透性的遗传易感性对于未来靶向治疗和预防 OHSS 很重要；ILK 信号和轴突引导信号的潜在作用需要通过功能研究来验证。