Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation

• Type of Material: Article
• Authors: Hari K. Somineni, Emory University; Suresh Venkateswaran, Emory University; Varun Kilaru, Emory University; Urko M. Marigorta, Georgia Institute of Technology; Angela Mo, Georgia Institute of Technology; David Okou, Emory University; Richard Kellermayer, Texas Childrens Hospital; Kajari Mondal, Emory University; Dawayland Cobb, Emory University; Thomas D. Walters, University of Toronto; Anne Griffiths, University of Toronto; Joshua D. Noe, Medical College of Wisconsin; Wallace V. Crandall, Ohio State University; Joel R. Rosh, Goryeb Childrens Hospital; David R. Mack, Children’s Hospital of Eastern Ontario IBD Centre and University of Ottawa, Ottawa; Melvin B. Heyman, University of California San Francisco; Susan S. Baker, University at Buffalo; Michael C. Stephens, Mayo Clinic; Robert N. Baldassano, University of Pennsylvania; James F. Markowitz, Northwell Health; Marla Dubinsky, Mt Sinai Hospital; Judy Cho, Mt Sinai Hospital; Jeffrey S. Hyams, Connecticut Childrens Medical Center; Lee A. Denson, Cincinnati Childrens Hospital Medical Center; Greg Gibson, Georgia Institute of Technology; David Cutler, Emory University; Karen Conneely, Emory University; Alicia Smith, Emory University; Subramaniam Kugathasan, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: W. B. Saunders Co-Elsevier Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 by the AGA Institute.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.gastro.2019.01.270
• Title of Journal or Parent Work: Gastroenterology
• Volume: 156
• Issue: 8
• Start Page: 2254
• End Page: +
• Grant/Funding Information: This work was supported by a research initiative grant from the Crohn’s and Colitis Foundation, New York, NY to the individual study institutions participating in the RISK study.; This research was also supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, under grant numbers R01-DK098231 and R01-DK087694 to S.K.
• Keywords: Risk; Epigenetic Alteration; Inflammatory Bowel Disease; Children; Life Sciences & Biomedicine; GWAS; Prediction; Wide association; Cancer; Cells; Gastroenterology & Hepatology; Index; Bowel disease; Immune; Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease (RISK) Study; Science & Technology
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology; Biology, Cell; Biology, Genetics

Abstract

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 progresses 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. Methods: We obtained blood samples from 164 pediatric patients (ages, 1–17 years) 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 were used as controls (n=74). DNA methylation patterns were analyzed at approximately 850,000 sites, in samples collected at time of diagnosis and 1–3 years later. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to development of or result from Crohn’s disease. Results: We identified 1189 CpGs 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 revealed 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 CpGs 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. Conclusions: Methylation patterns observed in blood samples from patients with Crohn’s disease accompany acute inflammation; with treatment, they 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.