INSERM, US14-Orphanet, 75014, Paris, France.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum, Sudan, 11121.
J Ovarian Res. 2023 Aug 5;16(1):155. doi: 10.1186/s13048-023-01159-5.
Women with polycystic ovarian syndrome (PCOS) have increased hypothalamic-pituitary-adrenal (HPA) axis activation, pro-inflammatory mediators, and psychological distress in response to stressors. In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in CRHR1 and CRHR2 genes may predispose to the mental-metabolic risk for PCOS.
We phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within CRHR1 and CRHR2 genes, respectively, 36 and 18 microarray-variants for parametric linkage to and/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2).
We detected 22 variants in CRHR1 and 1 variant in CRHR2 significantly (p < 0.05) linked to or in LD with PCOS across different inheritance models.
This is the first study to report CRHR1 and CRHR2 as novel risk genes in PCOS. In silico analysis predicted that the detected CRHR1 and CRHR2 risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, CRHR1- and CRHR2-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.
多囊卵巢综合征（PCOS）女性的下丘脑-垂体-肾上腺（HPA）轴激活、促炎介质和心理压力反应增加。在 PCOS 女性中，促肾上腺皮质激素释放激素（CRH）诱导 HPA 反应过度，可能由 CRH 受体（CRHR1 或 CRHR2）之一介导。CRHR1 和 CRHR2 均参与胰岛素分泌，CRHR1 和 CRHR2 基因的变体可能使 PCOS 具有精神代谢风险。
我们根据鹿特丹诊断标准对 212 个意大利 2 型糖尿病（T2D）家族进行了 PCOS 表型分析。我们分别在 CRHR1 和 CRHR2 基因中分析了 36 个和 18 个微阵列变体，以在隐性完全穿透（R1）和显性完全穿透（D1）模型下对 PCOS 进行参数连锁和/或连锁不平衡（LD）。随后，我们在不完全穿透显性（D2）和不完全穿透隐性（R2）模型下进行了二次分析。
我们在不同遗传模型下检测到 22 个 CRHR1 变体和 1 个 CRHR2 变体与 PCOS 显著（p < 0.05）连锁或处于 LD 状态。
这是第一项报道 CRHR1 和 CRHR2 为 PCOS 新风险基因的研究。计算机分析预测，检测到的 CRHR1 和 CRHR2 风险变体可能会促进卵巢中相关基因的负染色质激活，从而可能影响女性周期和排卵。然而，CRHR1 和 CRHR2 风险变体也可能导致皮质醇过多，并产生精神代谢的多效性效应。需要进行功能研究来确认基因和相关变体的致病性。
