Hari K Somineni1, Suresh Venkateswaran2, Varun Kilaru3, Urko M Marigorta4, Angela Mo4, David T Okou2, Richard Kellermayer5, Kajari Mondal2, Dawayland Cobb3, Thomas D Walters6, Anne Griffiths6, Joshua D Noe7, Wallace V Crandall8, Joel R Rosh9, David R Mack10, Melvin B Heyman11, Susan S Baker12, Michael C Stephens13, Robert N Baldassano14, James F Markowitz15, Marla C Dubinsky16, Judy Cho16, Jeffrey S Hyams17, Lee A Denson18, Greg Gibson4, David J Cutler19, Karen N Conneely20, Alicia K Smith21, Subra Kugathasan22. 1. 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. 2. Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia. 3. Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia. 4. Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, Georgia. 5. Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas. 6. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 7. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin. 8. Division of Pediatric Gastroenterology, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio. 9. Department of Pediatrics, Goryeb Children's Hospital, Morristown, New Jersey. 10. Department of Pediatrics, Children's Hospital of Eastern Ontario IBD Centre and University of Ottawa, Ottawa, Ontario, Canada. 11. Department of Pediatrics, University of California, San Francisco, San Francisco, California. 12. Department of Digestive Diseases and Nutrition Center, University at Buffalo, Buffalo, New York. 13. Department of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota. 14. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania. 15. Department of Pediatrics, Northwell Health, New York, New York. 16. Department of Pediatrics, Mount Sinai Hospital, New York, New York. 17. Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut. 18. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 19. Department of Human Genetics, Emory University, Atlanta, Georgia. 20. Genetics and Molecular Biology Program, Emory University, Atlanta, Georgia; Department of Human Genetics, Emory University, Atlanta, Georgia. 21. Genetics and Molecular Biology Program, Emory University, Atlanta, Georgia; Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia. 22. 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; Department of Human Genetics, Emory University, Atlanta, Georgia. Electronic address: skugath@emory.edu.
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 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Keywords:
Children; Epigenetic Alteration; Inflammatory Bowel Disease; Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease (RISK) Study
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