Molecular Landscape of Pelvic Organ Prolapse Provides Insights into Disease Etiology.
Molecular Landscape of Pelvic Organ Prolapse Provides Insights into Disease Etiology.
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盆腔器官脱垂的分子图谱为疾病病因学提供见解。
DOI：
10.3390/ijms24076087
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发表时间：
2023-03-23
影响因子：
5.6
通讯作者：
Poelmans, Geert
中科院分区：
文献类型：
--
作者：
Kluivers, Kirsten B.;Lince, Sabrina L.;Ruiz-Zapata, Alejandra M.;Post, Wilke M.;Cartwright, Rufus;Kerkhof, Manon H.;Widomska, Joanna;De Witte, Ward;Pecanka, Jakub;Kiemeney, Lambertus A.;Vermeulen, Sita H.;Goeman, Jelle J.;Allen-Brady, Kristina;Oosterwijk, Egbert;Poelmans, Geert
盆腔器官脱垂(POP)是女性的主要保健负担，但其潜在的病理生理机制尚未阐明。我们首先使用病例对照设计在526名患有POP的妇女和960名对照妇女中进行外显子组芯片研究，以确定与该疾病相关的单核苷酸变异(SNV)。然后，我们将来自外显子芯片研究的POP候选蛋白与其他POP候选分子之间的功能相互作用整合到一个分子图景中。我们在54个基因中发现了POP和SNV之间的显著关联。其中26个基因编码的蛋白质与43个其他POP候选分子一起符合分子格局。POP位于泌尿生殖道上皮细胞和成纤维细胞内及其周围，包含四个相互作用的生物学过程--上皮-间充质转化、免疫反应、细胞外基质调节和成纤维细胞功能--受性激素和TGFB1调节。我们的发现得到了来自独立POP队列的差异基因表达数据的丰富分析的证实。最后，基于景观，并使用来自POP女性的阴道成纤维细胞，我们预测并表明二甲双胍以有益的方向改变了这些成纤维细胞中的基因表达。总而言之，我们集成的POP分子图景提供了对疾病潜在的生物学过程的洞察和新治疗方法的线索。
Pelvic organ prolapse (POP) represents a major health care burden in women, but its underlying pathophysiological mechanisms have not been elucidated. We first used a case-control design to perform an exome chip study in 526 women with POP and 960 control women to identify single nucleotide variants (SNVs) associated with the disease. We then integrated the functional interactions between the POP candidate proteins derived from the exome chip study and other POP candidate molecules into a molecular landscape. We found significant associations between POP and SNVs in 54 genes. The proteins encoded by 26 of these genes fit into the molecular landscape, together with 43 other POP candidate molecules. The POP landscape is located in and around epithelial cells and fibroblasts of the urogenital tract and harbors four interacting biological processes—epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function—that are regulated by sex hormones and TGFB1. Our findings were corroborated by enrichment analyses of differential gene expression data from an independent POP cohort. Lastly, based on the landscape and using vaginal fibroblasts from women with POP, we predicted and showed that metformin alters gene expression in these fibroblasts in a beneficial direction. In conclusion, our integrated molecular landscape of POP provides insights into the biological processes underlying the disease and clues towards novel treatments.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
9.8
作者：
Allen-Brady, Kristina;Norton, Peggy A.;Cannon-Albright, Lisa A.
通讯作者：
Cannon-Albright, Lisa A.
二甲双胍通过抑制 TGF-β 信号通路减轻吉非替尼诱导的肺纤维化恶化
影响因子：
--
作者：
Li L;Huang W;Li K;Zhang K;Lin C;Han R;Lu C;Wang Y;Chen H;Sun F;He Y
通讯作者：
He Y
影响因子：
7.7
作者：
Galesloot, Tessel E.;Vermeulen, Sita H.;Kiemeney, Lambertus A. L. M.
通讯作者：
Kiemeney, Lambertus A. L. M.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay