Genetics and Molecular Biology Program, Emory University, Atlanta, Georgia; Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
Gastroenterology. 2019 Jun;156(8):2254-2265.e3. doi: 10.1053/j.gastro.2019.01.270. Epub 2019 Feb 16.
BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression.
We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease.
We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease.
Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.
克罗恩病是一种反复发作、缓解的炎症性疾病，其临床表现具有多变性。虽然大多数患者表现出炎症表型（B1），但大约 20%的患者在 5 年内会迅速发展为复杂疾病，包括狭窄（B2）。我们分析了诊断时和随后时间点患有克罗恩病的儿科患者的血液样本中的 DNA 甲基化模式，以确定与疾病发展和进展相关并可能导致疾病发展和进展的变化。
我们从参加北美研究的 164 名患有克罗恩病（B1 或 B2）的儿科患者（1-17 岁）中获得了血液样本，并对他们进行了 5 年的随访。没有肠道炎症或症状的参与者作为对照（n=74）。在大约 850000 个位点处，在诊断时和 1-3 年后收集的样本中分析了 DNA 甲基化模式。我们使用遗传关联和孟德尔随机化的概念来确定 DNA 甲基化模式的变化，这些变化可能导致或源于克罗恩病的发生。
我们在克罗恩病患者（诊断时）和对照之间鉴定出 1189 个 5'-胞嘧啶-磷酸-鸟嘌呤-3'（CpG）位点存在差异甲基化。这些位点的甲基化变化与血浆 C 反应蛋白水平相关。比较克罗恩病诊断时和随访期间收集的 DNA 甲基化谱显示，在治疗期间，在克罗恩病诊断时鉴定出的甲基化谱的改变更接近对照组的模式，无论疾病是否进展为 B2。我们在 3 个 CpG 位点发现了可能导致克罗恩病发生的甲基化变化。与克罗恩病相关的大多数 CpG 甲基化变化随着炎症的治疗而消失，可能是克罗恩病的结果。
克罗恩病患者血液样本中观察到的甲基化模式伴随着急性炎症；随着治疗，这些变化会类似于没有肠道炎症的患者的甲基化模式。这些发现表明，在血液样本中观察到的与克罗恩病相关的 DNA 甲基化模式是疾病炎症特征的结果，不太可能导致疾病的发展或进展。
