美国哈佛医学院Pradeep Natarajan小组揭示克隆性造血和慢性肝病的风险。这一研究成果于2023年4月12日在线发表在国际学术期刊《自然》上。
研究人员对来自4个独立队列的214563名具有全外显子组测序数据的个体（弗雷明汉心脏研究、动脉硬化风险社区研究、英国生物银行和马萨诸塞州布里格姆生物银行），进行了不确定潜力的克隆造血（CHIP）与慢性肝病之间的关联研究。CHIP与流行和发生慢性肝病的风险增加有关（几率=2.01，95%置信区间（95%CI）[1.46，2.79]；P<0.001）。与没有CHIP的人相比，患有CHIP的人更有可能表现出可通过磁共振成像检测到的肝脏炎症和纤维化（几率比=1.74，95%CI [1.16, 2.60]；P=0.007）。
为了评估潜在的因果关系，孟德尔随机化分析显示，CHIP的遗传倾向与更大的慢性肝病风险有关（几率=2.37，95%CI [1.57, 3.6]；P<0.001）。在非酒精性脂肪性肝炎的饮食模型中，移植了Tet2缺陷造血细胞的小鼠表现出更严重的肝脏炎症和纤维化。这些影响是由NLRP3炎症体和Tet2缺陷的巨噬细胞中下游炎症细胞因子表达水平增加所介导的。总之，克隆性造血与肝脏炎症和慢性肝病进展的风险升高有关，是通过反常的炎症反应来实现。
据介绍，慢性肝病是世界范围内的一个主要公共卫生负担。尽管存在不同的病因和肝脏损伤机制，但慢性肝病的发展遵循一个共同的肝脏炎症、损伤和纤维化的途径。
附：英文原文
Title: Clonal haematopoiesis and risk of chronic liver disease
Author: Wong, Waihay J., Emdin, Connor, Bick, Alexander G., Zekavat, Seyedeh M., Niroula, Abhishek, Pirruccello, James P., Dichtel, Laura, Griffin, Gabriel, Uddin, Md Mesbah, Gibson, Christopher J., Kovalcik, Veronica, Lin, Amy E., McConkey, Marie E., Vromman, Amelie, Sellar, Rob S., Kim, Peter G., Agrawal, Mridul, Weinstock, Joshua, Long, Michelle T., Yu, Bing, Banerjee, Rajarshi, Nicholls, Rowan C., Dennis, Andrea, Kelly, Matt, Loh, Po-Ru, McCarroll, Steve, Boerwinkle, Eric, Vasan, Ramachandran S., Jaiswal, Siddhartha, Johnson, Andrew D., Chung, Raymond T., Corey, Kathleen, Levy, Daniel, Ballantyne, Christie, Ebert, Benjamin L., Natarajan, Pradeep
Issue&Volume: 2023-04-12
Abstract: Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio=2.01, 95% confidence interval (95%CI)[1.46,2.79]; P<0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio=1.74, 95%CI[1.16,2.60]; P=0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio=2.37, 95% CI[1.57,3.6]; P<0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.
DOI: 10.1038/s41586-023-05857-4
Source: https://www.nature.com/articles/s41586-023-05857-4
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
