Garibaldi-Ríos Asbiel Felipe, Rodríguez-Gutiérrez Perla Graciela, García-Díaz Jesús Magdiel, Zúñiga-González Guillermo Moisés, Figuera Luis E, Gómez-Meda Belinda Claudia, Puebla-Pérez Ana María, Dávalos-Rodríguez Ingrid Patricia, Torres-Mendoza Blanca Miriam, Gutiérrez-Hurtado Itzae Adonai, Gallegos-Arreola Martha Patricia
División de Genética, Centro de Investigación Biomédica de Occidente (CIBO), Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico.
Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico.
Diseases. 2025 Aug 6;13(8):248. doi: 10.3390/diseases13080248.
Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the ectopic presence of endometrial-like tissue. Although genome-wide association studies (GWAS) have identified susceptibility variants, their tissue-specific regulatory impact remains poorly understood.
To functionally characterize endometriosis-associated variants by exploring their regulatory effects as expression quantitative trait loci (eQTLs) across six physiologically relevant tissues: peripheral blood, sigmoid colon, ileum, ovary, uterus, and vagina.
GWAS-identified variants were cross-referenced with tissue-specific eQTL data from the GTEx v8 database. We prioritized genes either frequently regulated by eQTLs or showing the strongest regulatory effects (based on slope values, which indicate the direction and magnitude of the effect on gene expression). Functional interpretation was performed using MSigDB Hallmark gene sets and Cancer Hallmarks gene collections.
A tissue specificity was observed in the regulatory profiles of eQTL-associated genes. In the colon, ileum, and peripheral blood, immune and epithelial signaling genes predominated. In contrast, reproductive tissues showed the enrichment of genes involved in hormonal response, tissue remodeling, and adhesion. Key regulators such as , , and were consistently linked to hallmark pathways, including immune evasion, angiogenesis, and proliferative signaling. Notably, a substantial subset of regulated genes was not associated with any known pathway, indicating potential novel regulatory mechanisms.
This integrative approach highlights the com-plexity of tissue-specific gene regulation mediated by endometriosis-associated variants. Our findings provide a functional framework to prioritize candidate genes and support new mechanistic hypotheses for the molecular pathophysiology of endometriosis.
子宫内膜异位症是一种慢性、雌激素依赖性炎症性疾病，其特征是子宫内膜样组织的异位存在。尽管全基因组关联研究（GWAS）已经确定了易感变异，但它们对组织特异性的调控影响仍知之甚少。
通过探索子宫内膜异位症相关变异在六个生理相关组织（外周血、乙状结肠、回肠、卵巢、子宫和阴道）中作为表达数量性状基因座（eQTL）的调控作用，对其进行功能表征。
将GWAS确定的变异与来自GTEx v8数据库的组织特异性eQTL数据进行交叉参考。我们优先考虑那些经常受eQTL调控或显示出最强调控作用的基因（基于斜率值，斜率值表明对基因表达的影响方向和大小）。使用MSigDB标志性基因集和癌症标志性基因集合进行功能解释。
在eQTL相关基因的调控谱中观察到组织特异性。在结肠、回肠和外周血中，免疫和上皮信号基因占主导。相比之下，生殖组织中参与激素反应、组织重塑和黏附的基因富集。关键调节因子如 、 和 始终与包括免疫逃逸、血管生成和增殖信号传导在内的标志性通路相关联。值得注意的是，相当一部分受调控的基因与任何已知通路均无关联，这表明存在潜在的新调控机制。
这种综合方法突出了由子宫内膜异位症相关变异介导的组织特异性基因调控的复杂性。我们的研究结果提供了一个功能框架，用于对候选基因进行优先排序，并支持关于子宫内膜异位症分子病理生理学的新机制假说。
