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)

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...

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Published in:Cellular and molecular gastroenterology and hepatology 2023-01, Vol.16 (3), p.431-450
Main Authors: Ventham, Nicholas T., Kennedy, Nicholas A., Kalla, Rahul, Adams, Alex T., Noble, Alexandra, Ennis, Holly, Arnott, Ian, Cahill, Aiden, Smith, Malcolm, Ahmad, Tariq, Subramanian, Sreedhar, Travis, Simon, Morris, John, Hamlin, John, Dhar, Anjan, Nwokolo, Chuka, Creed, Tom, Bloom, Stuart, Yousif, Mohamed, Thomas, Linzi, Campbell, Simon, Lewis, Stephen J., Sebastian, Shaji, Sen, Sandip, Lal, Simon, Hawkey, Chris, Murray, Charles, Cummings, Fraser, Goh, Jason, Lindsay, James O., Arebi, Naila, Potts, Lindsay, McKinley, Aileen J., Thomson, John M., Todd, John A., Collie, Mhairi, Mowat, Ashley, Gaya, Daniel R., Winter, Jack, Naismith, Graham D., Keerie, Catriona, Lewis, Steff, Prescott, Robin J., Campbell, Harry, McGovern, Dermot P.B., Annese, Vito, Zoldoš, Vlatka, Permberton, Iain K., Wuhrer, Manfred, Kolarich, Daniel, Fernandes, Daryl L., Theorodorou, Evropi, Daniel I. Spencer, Victoria Merrick, Gardner, Richard A., Doran, Ray, Shubhakar, Archana, Boyapati, Ray, Rudan, Igor, Lionetti, Paolo, Akmačić, Irena Trbojević, Krištić, Jasminka, Vuč ković, Frano, Štambuk, Jerko, Novokmet, Mislav, Pučić-Baković, Maja, Gornik, Olga, Andriulli, Angelo, Cantoro, Laura, Sturniolo, Giancarlo, Fiorino, Gionata, Manetti, Natalia, Latiano, Anna, Kohn, Anna, D’Inca`, Renata, Danese, Silvio, Arnott, Ian D., Noble, Colin L., Lees, Charlie W., Shand, Alan G., Murphy, Lee, Gibson, Jude, Evenden, Louise, Wrobel, Nicola, Gilchrist, Tamara, Fawkes, Angie, Kammeijer, Guinevere S.M., Clerc, Florent, de Haan, Noortje, Vojta, Aleksandar, Samaržija, Ivana, Markulin, Dora, Klasić, Marija, Dobrinić, Paula, Aulchenko, Yurii, van den Heuve, Tim, Jonkers, Daisy, Pierik, Marieke, Mowat, Craig, Dunlop, Malcolm G., Satsangi, Jack
Format: Article
Language:English
Subjects:
Adult
Aging
Child
Child, Preschool
Crohn Disease - genetics
Crohn Disease - surgery
Crohn's disease
DNA methylation
DNA Methylation - genetics
Epigenesis, Genetic
Epigenetics
Genome-Wide Association Study - methods
Humans
Inflammatory bowel disease
Inflammatory Bowel Diseases - genetics
Membrane Proteins - genetics
Original Research
Surgery
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Summary: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. 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). 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 previousl
ISSN:2352-345X
2352-345X
DOI:10.1016/j.jcmgh.2023.06.001