Federica Genovese , Cecilie Bager , Peder Frederiksen , Dario Vazquez , Jannie Marie Bülow Sand , R Gisli Jenkins , Toby M. Maher , Iain D. Stewart , Philip L. Molyneaux , William A Fahy , Louise V. Wain , Jørgen Vestbo , Carmel Nanthakumar , Saher Burhan Shaker , Nils Hoyer , Diana Julie Leeming , Jacob George , Jonel Trebicka , Daniel Guldager Kring Rasmussen , Michael K. Hansen , Detlef Schuppan
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Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PRO<img>C6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available.</p><p>In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (<em>N</em> = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75—2.52) for a 2-fold increase in PRO<img>C6, with some heterogeneity observed between the studies (I<sup>2</sup>=70 %).</p><p>This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. 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引用次数: 0
摘要
成纤维细胞活动导致的纤维化是大多数慢性疾病发病率和死亡率的重要原因。内营养素是高度活化的成纤维细胞加工 VI 型胶原蛋白时产生的一种信号分子，它参与了纤维化组织的重塑。内营养素的循环水平与多种慢性疾病的死亡风险增加有关。我们进行了一项系统性文献综述，从 2012 年至 2023 年 1 月间发表的、报道循环内营养素（PRO-C6）与死亡率之间关系的原始论文中收集证据。在对年龄、性别和体重指数（如有）进行调整后，一项评估 PRO-C6 与死亡率关系的个体患者数据 (IPD) 荟萃分析（PROSPERO 注册号：CRD42023340215）纳入了研究作者可获得数据的队列。IPD荟萃分析包括16个不同非传染性慢性疾病（NCCDs）患者队列（N=15205），PRO-C6增加2倍时，3年全因死亡率的总危险比估计为2.10（95% CI 1.75-2.52），研究之间存在一定的异质性（I2=70%）。这项荟萃分析是第一项记录成纤维细胞活性（通过循环内营养素量化）与多种 NCCDs 死亡率独立相关的研究。这表明，无论哪种疾病，间质组织重塑以及由此产生的成纤维细胞活性在不良临床结果中都起着核心作用，药物开发人员应迫切考虑将其作为治疗目标。
The fibroblast hormone Endotrophin is a biomarker of mortality in chronic diseases
Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases.
We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PROC6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PROC6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available.
In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75—2.52) for a 2-fold increase in PROC6, with some heterogeneity observed between the studies (I2=70 %).
This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat.
期刊介绍：
Matrix Biology (established in 1980 as Collagen and Related Research) is a cutting-edge journal that is devoted to publishing the latest results in matrix biology research. We welcome articles that reside at the nexus of understanding the cellular and molecular pathophysiology of the extracellular matrix. Matrix Biology focusses on solving elusive questions, opening new avenues of thought and discovery, and challenging longstanding biological paradigms.
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