Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Gynaecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, China.
Front Endocrinol (Lausanne). 2024 Jul 5;15:1416978. doi: 10.3389/fendo.2024.1416978. eCollection 2024.
Endometriosis (EM) is a chronic painful condition that predominantly affects women of reproductive age. Currently, surgery or medication can only provide limited symptom relief. This study used a comprehensive genetic analytical approach to explore potential drug targets for EM in the plasma proteome.
In this study, 2,923 plasma proteins were selected as exposure and EM as outcome for two-sample Mendelian randomization (MR) analyses. The plasma proteomic data were derived from the UK Biobank Pharmaceutical Proteomics Project (UKB-PPP), while the EM dataset from the FinnGen consortium R10 release data. Several sensitivity analyses were performed, including summary-data-based MR (SMR) analyses, heterogeneity in dependent instruments (HEIDI) test, reverse MR analyses, steiger detection test, and bayesian co-localization analyses. Furthermore, proteome-wide association study (PWAS) and single-cell transcriptomic analyses were also conducted to validate the findings.
Six significant (p < 3.06 × 10) plasma protein-EM pairs were identified by MR analyses. These included EPHB4 (OR = 1.40, 95% CI: 1.20 - 1.63), FSHB (OR = 3.91, 95% CI: 3.13 - 4.87), RSPO3 (OR = 1.60, 95% CI: 1.38 - 1.86), SEZ6L2 (OR = 1.44, 95% CI: 1.23 - 1.68) and WASHC3 (OR = 2.00, 95% CI: 1.54 - 2.59) were identified as risk factors, whereas KDR (OR = 0.80, 95% CI: 0.75 - 0.90) was found to be a protective factor. All six plasma proteins passed the SMR test (P < 8.33 × 10), but only four plasma proteins passed the HEIDI heterogeneity test (PHEIDI > 0.05), namely FSHB, RSPO3, SEZ6L2 and EPHB4. These four proteins showed strong evidence of co-localization (PPH4 > 0.7). In particular, RSPO3 and EPHB4 were replicated in the validated PWAS. Single-cell analyses revealed high expression of SEZ6L2 and EPHB4 in stromal and epithelial cells within EM lesions, while RSPO3 exhibited elevated expression in stromal cells and fibroblasts.
Our study identified FSHB, RSPO3, SEZ6L2, and EPHB4 as potential drug targets for EM and highlighted the critical role of stromal and epithelial cells in disease development. These findings provide new insights into the diagnosis and treatment of EM.
子宫内膜异位症（EM）是一种慢性疼痛性疾病，主要影响育龄妇女。目前，手术或药物只能提供有限的症状缓解。本研究采用综合遗传分析方法探索 EM 在血浆蛋白质组中的潜在药物靶点。
本研究中，选择 2923 种血浆蛋白作为暴露因素，EM 作为结局进行两样本孟德尔随机化（MR）分析。血浆蛋白质组数据来自英国生物库制药蛋白质组学项目（UKB-PPP），而 EM 数据集来自 FinnGen 联盟 R10 发布数据。进行了几项敏感性分析，包括基于汇总数据的 MR（SMR）分析、依赖工具的异质性（HEIDI）检验、反向 MR 分析、斯蒂格检测试验和贝叶斯共定位分析。此外，还进行了全蛋白质组关联研究（PWAS）和单细胞转录组分析，以验证研究结果。
MR 分析鉴定出 6 个具有统计学意义的（p < 3.06×10）血浆蛋白-EM 对。这些包括 EPHB4（OR = 1.40，95% CI：1.20-1.63）、FSHB（OR = 3.91，95% CI：3.13-4.87）、RSPO3（OR = 1.60，95% CI：1.38-1.86）、SEZ6L2（OR = 1.44，95% CI：1.23-1.68）和 WASHC3（OR = 2.00，95% CI：1.54-2.59）被确定为危险因素，而 KDR（OR = 0.80，95% CI：0.75-0.90）被认为是保护因素。所有 6 种血浆蛋白均通过 SMR 检验（P < 8.33×10），但只有 4 种血浆蛋白通过 HEIDI 异质性检验（PHEIDI > 0.05），即 FSHB、RSPO3、SEZ6L2 和 EPHB4。这四种蛋白显示出强烈的共定位证据（PPH4 > 0.7）。特别是，RSPO3 和 EPHB4 在验证的 PWAS 中得到了复制。单细胞分析显示，SEZ6L2 和 EPHB4 在 EM 病变的基质和上皮细胞中高表达，而 RSPO3 在基质细胞和成纤维细胞中表达升高。
本研究确定了 FSHB、RSPO3、SEZ6L2 和 EPHB4 作为 EM 的潜在药物靶点，并强调了基质和上皮细胞在疾病发展中的关键作用。这些发现为 EM 的诊断和治疗提供了新的见解。
