Genome-Wide Methylation Profiling in 229 Patients With Crohn’s Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn’s Disease (TOPPIC)Summary

Background & Aims: DNA methylation alterations may provide important insights into gene-environment interaction in cancer, aging, and complex diseases, such as inflammatory bowel disease (IBD). We aim first to determine whether the circulating DNA methylome in patients requiring surgery may pred...

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Published in:	Cellular and molecular gastroenterology and hepatology Vol. 16; no. 3; pp. 431 - 450
Main Authors:	Nicholas T. Ventham, Nicholas A. Kennedy, Rahul Kalla, Alex T. Adams, Alexandra Noble, Holly Ennis, Craig Mowat, Malcolm G. Dunlop, Jack Satsangi, Ian Arnott, Aiden Cahill, Malcolm Smith, Tariq Ahmad, Sreedhar Subramanian, Simon Travis, John Morris, John Hamlin, Anjan Dhar, Chuka Nwokolo, Cathryn Edwards, Tom Creed, Stuart Bloom, Mohamed Yousif, Linzi Thomas, Simon Campbell, Stephen J. Lewis, Shaji Sebastian, Sandip Sen, Simon Lal, Chris Hawkey, Charles Murray, Fraser Cummings, Jason Goh, James O. Lindsay, Naila Arebi, Lindsay Potts, Aileen J. McKinley, John M. Thomson, John A. Todd, Mhairi Collie, Ashley Mowat, Daniel R. Gaya, Jack Winter, Graham D. Naismith, Catriona Keerie, Steff Lewis, Robin J. Prescott, Gordan Lauc, Harry Campbell, Dermot P.B. McGovern, Vito Annese, Vlatka Zoldoš, Iain K. Permberton, Manfred Wuhrer, Daniel Kolarich, Daryl L. Fernandes, Evropi Theorodorou, Victoria Merrick Daniel I. Spencer, Richard A. Gardner, Ray Doran, Archana Shubhakar, Ray Boyapati, Igor Rudan, Paolo Lionetti, Irena Trbojević Akmačić, Jasminka Krištić, Frano Vuč ković, Jerko Štambuk, Mislav Novokmet, Maja Pučić-Baković, Olga Gornik, Angelo Andriulli, Laura Cantoro, Giancarlo Sturniolo, Gionata Fiorino, Natalia Manetti, Anna Latiano, Anna Kohn, Renata D’Inca`, Silvio Danese, Ian D. Arnott, Colin L. Noble, Charlie W. Lees, Alan G. Shand, Gwo-Tzer Ho, Lee Murphy, Jude Gibson, Louise Evenden, Nicola Wrobel, Tamara Gilchrist, Angie Fawkes, Guinevere S.M. Kammeijer, Florent Clerc, Noortje de Haan, Aleksandar Vojta, Ivana Samaržija, Dora Markulin, Marija Klasić, Paula Dobrinić
Format:	Journal Article
Language:	English
Published:	Elsevier 01-01-2023
Subjects:	Aging Crohn's disease DNA methylation Epigenetics Inflammatory bowel disease Surgery
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Summary:	Background & Aims: DNA methylation alterations may provide important insights into gene-environment interaction in cancer, aging, and complex diseases, such as inflammatory bowel disease (IBD). We aim first to determine whether the circulating DNA methylome in patients requiring surgery may predict Crohn’s disease (CD) recurrence following intestinal resection; and second to compare the circulating methylome seen in patients with established CD with that we had reported in a series of inception cohorts. Methods: TOPPIC was a placebo-controlled, randomized controlled trial of 6-mercaptopurine at 29 UK centers in patients with CD undergoing ileocolic resection between 2008 and 2012. Genomic DNA was extracted from whole blood samples from 229 of the 240 patients taken before intestinal surgery and analyzed using 450KHumanMethylation and Infinium Omni Express Exome arrays (Illumina, San Diego, CA). Coprimary objectives were to determine whether methylation alterations may predict clinical disease recurrence; and to assess whether the epigenetic alterations previously reported in newly diagnosed IBD were present in the patients with CD recruited into the TOPPIC study. Differential methylation and variance analysis was performed comparing patients with and without clinical evidence of recurrence. Secondary analyses included investigation of methylation associations with smoking, genotype (MeQTLs), and chronologic age. Validation of our previously published case-control observation of the methylome was performed using historical control data (CD, n = 123; Control, n = 198). Results: CD recurrence in patients following surgery is associated with 5 differentially methylated positions (Holm P < .05), including probes mapping to WHSC1 (P = 4.1 × 10-9, Holm P = .002) and EFNA3 (P = 4.9 × 10-8, Holm P = .02). Five differentially variable positions are demonstrated in the group of patients with evidence of disease recurrence including a probe mapping to MAD1L1 (P = 6.4 × 10-5). DNA methylation clock analyses demonstrated significant age acceleration in CD compared with control subjects (GrimAge + 2 years; 95% confidence interval, 1.2–2.7 years), with some evidence for accelerated aging in patients with CD with disease recurrence following surgery (GrimAge +1.04 years; 95% confidence interval, -0.04 to 2.22). Significant methylation differences between CD cases and control subjects were seen by comparing this cohort in conjunction with previously published control data, including validation of our previously described differentially methylated positions (RPS6KA2 P = 1.2 × 10-19, SBNO2 = 1.2 × 10-11) and regions (TXK [false discovery rate, P = 3.6 × 10-14], WRAP73 [false discovery rate, P = 1.9 × 10-9], VMP1 [false discovery rate, P = 1.7 × 10-7], and ITGB2 [false discovery rate, P = 1.4 × 10-7]). Conclusions: We demonstrate differential methylation and differentially variable methylation in patients developing clinical recurrence within 3 years of surgery. Moreover, we report replication of the CD-associated methylome, previously characterized only in adult and pediatric inception cohorts, in patients with medically refractory disease needing surgery.
ISSN:	2352-345X 2352-345X