Tan Hangjing, Zhao Jing, Wang Baisheng, Li Yanping
Department of Reproductive Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan Province, China.
J Ovarian Res. 2025 Jun 10;18(1):127. doi: 10.1186/s13048-025-01696-1.
Early diagnosis and early delivery are the main strategies for the treatment of premature ovarian insufficiency (POI). However, POI warning markers, especially those that can be detected through noninvasive methods, are very limited; therefore, the identification of noninvasive markers for POI is urgent.
We acquired POI GWAS summary statistics from the FinnGen database. The metabolome, circulating plasma proteins, gut microbiota, immunophenotypes, circulating microRNAs (miRNAs), and two proteomes were obtained for two-sample Mendelian randomization (MR). Specifically, we employed inverse variance weighted (IVW) as the main method to calculate the MR effect estimates. eQTL data (from the eQTLGen Consortium) were employed for SMR. Hub genes were identified using the String database and Cytoscape software. Potential mechanisms of POI were identified via pathway enrichment analysis of the identified genes and miRNAs.
Three metabolites (sphinganine-1-phosphate levels, X-23636 levels, 4-methyl-2-oxopentanoate levels), two circulating plasma proteins (fibroblast growth factor 23 levels, neurotrophin-3 levels), one gut microbiota (faecalibacterium abundance), one immunophenotype (HVEM on naive CD8 + T cells), 23 miRNAs (miR-500a-3p, miR-555, miR-584-5p, miR-642a-5p, miR-671-3p, miR-1324, miR-6870-3p, miR-1468-5p, miR-146a-3p, miR-221-3p, miR-3121-5p, miR-3184-3p, miR-3185, miR-335-5p, miR-4302, miR-4506, miR-6808-5p, miR-6894-5p, miR-145-5p, miR-149-3p, miR-23a-3p, miR-3141, and miR-374b-5p), and three hub genes (ESR1, ERBB2, and GART) serve as warning markers for POI. Enrichment analysis indicated that pathways such as glutathione metabolism and the PI3 kinase pathway may be involved in mechanisms regulating POI.
Our results are the first to identify noninvasive predictors for POI via MR, providing contributions for early warning and fertility guidance for clinical POI patients.
早期诊断和早期分娩是治疗卵巢早衰（POI）的主要策略。然而，POI的预警标志物非常有限，尤其是那些可通过非侵入性方法检测到的标志物；因此，迫切需要鉴定POI的非侵入性标志物。
我们从芬兰基因数据库获取了POI全基因组关联研究（GWAS）汇总统计数据。获取代谢组、循环血浆蛋白、肠道微生物群、免疫表型、循环微小RNA（miRNA）以及两个蛋白质组用于两样本孟德尔随机化（MR）分析。具体而言，我们采用逆方差加权（IVW）作为主要方法来计算MR效应估计值。使用表达数量性状基因座（eQTL）数据（来自eQTLGen联盟）进行共定位分析（SMR）。使用String数据库和Cytoscape软件鉴定枢纽基因。通过对鉴定出的基因和miRNA进行通路富集分析，确定POI的潜在机制。
三种代谢物（鞘氨醇-1-磷酸水平、X-23636水平、4-甲基-2-氧代戊酸水平）、两种循环血浆蛋白（成纤维细胞生长因子23水平、神经营养因子3水平）、一种肠道微生物群（粪杆菌丰度）、一种免疫表型（初始CD8 + T细胞上的疱疹病毒侵入介质（HVEM））、23种miRNA（miR-500a-3p、miR-555、miR-584-5p、miR-642a-5p、miR-671-3p、miR-1324、miR-6870-3p、miR-1468-5p、miR-146a-3p、miR-221-3p、miR-3121-5p、miR-3184-3p、miR-3185、miR-335-5p、miR-4302、miR-4506、miR-6808-5p、miR-6894-5p、miR-145-5p、miR-149-3p、miR-23a-3p、miR-3141和miR-374b-5p）以及三个枢纽基因（雌激素受体1（ESR1）、表皮生长因子受体2（ERBB2）和甘氨酰胺核糖核苷酸转甲酰基酶（GART））可作为POI的预警标志物。富集分析表明，谷胱甘肽代谢和PI3激酶途径等通路可能参与调节POI的机制。
我们的研究结果首次通过MR鉴定出POI的非侵入性预测指标，为临床POI患者的早期预警和生育指导提供了依据。
