Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease.
Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease.
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DOI：
10.1136/gutjnl-2016-311526
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发表时间：
2017-07
期刊：
影响因子：
24.5
通讯作者：
Mann J
中科院分区：
文献类型：
--
作者：
Hardy T;Zeybel M;Day CP;Dipper C;Masson S;McPherson S;Henderson E;Tiniakos D;White S;French J;Mann DA;Anstee QM;Mann J
肝活检是目前评价非酒精性脂肪性肝病（NAFLD）患者肝纤维化的最可靠方法。其固有的风险限制了其广泛使用。最近研究表明，过氧化物酶体增殖物激活受体γ（PPARγ）基因启动子的差异性肝脏DNA甲基化可根据纤维化严重程度对患者进行分层，但需要进入肝脏组织。本研究的目的是评估是否可以在人血浆中检测到循环DNA的DNA甲基化，并可能用于对NAFLD患者的肝纤维化严重程度进行分层。从泰恩河畔纽卡斯尔医院NHS基金会信托的肝脏和胃肠病诊所招募活检证实的NAFLD患者和年龄匹配的对照组。通过焦磷酸测序定量评估血浆无细胞循环DNA的PPARγ甲基化。通过焦磷酸测序NAFLD外植体组织定量评估肝脏DNA甲基化，进行激光捕获显微切割（LCM）。酒精性肝病（ALD）患者也进行了血浆DNA和LCM焦磷酸测序。纳入了26例经活检证实的NAFLD患者。定量血浆DNA甲基化的过氧化物酶体增殖物激活受体γ分层患者为轻度（Kleiner 1-2）和重度（Kleiner 3-4）纤维化（CpG 1：63% vs 86%，p<0.05; CpG 2：51% vs 65% p>0.05）。血浆DNA中PPARγ启动子的超甲基化与肝细胞而不是肌成纤维细胞DNA甲基化的变化相关。在ALD肝硬化患者中证实了类似的结果。在人血浆的游离DNA池中可以检测到PPARγ启动子的差异DNA甲基化。通过进一步验证，血浆PPARγ DNA甲基化可能用于非侵入性分层NAFLD患者的肝纤维化严重程度。血浆DNA甲基化特征反映了与纤维化肝病相关的分子病理学。
Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD. Patients with biopsy-proven NAFLD and age-matched controls were recruited from the liver and gastroenterology clinics at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Plasma cell-free circulating DNA methylation of PPARγ was quantitatively assessed by pyrosequencing. Liver DNA methylation was quantitatively assessed by pyrosequencing NAFLD explant tissue, subjected to laser capture microdissection (LCM). Patients with alcoholic liver disease (ALD) were also subjected to plasma DNA and LCM pyrosequencing. 26 patients with biopsy-proven NAFLD were included. Quantitative plasma DNA methylation of PPARγ stratified patients into mild (Kleiner 1–2) and severe (Kleiner 3–4) fibrosis (CpG1: 63% vs 86%, p<0.05; CpG2: 51% vs 65% p>0.05). Hypermethylation at the PPARγ promoter of plasma DNA correlated with changes in hepatocellular rather than myofibroblast DNA methylation. Similar results were demonstrated in patients with ALD cirrhosis. Differential DNA methylation at the PPARγ promoter can be detected within the pool of cell-free DNA of human plasma. With further validation, plasma DNA methylation of PPARγ could potentially be used to non-invasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease.
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