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)
Ventham NT., Kennedy NA., Kalla R., Adams AT., Noble A., Ennis H., Arnott I., Cahill A., Smith M., Ahmad T., Subramanian S., Travis S., Morris J., Hamlin J., Dhar A., Nwokolo C., Edwards C., Creed T., Bloom S., Yousif M., Thomas L., Campbell S., Lewis SJ., Sebastian S., Sen S., Lal S., Hawkey C., Murray C., Cummings F., Goh J., Lindsay JO., Arebi N., Potts L., McKinley AJ., Thomson JM., Todd JA., Collie M., Mowat A., Gaya DR., Winter J., Naismith GD., Keerie C., Lewis S., Prescott RJ., Lauc G., Campbell H., McGovern DPB., Annese V., Zoldoš V., Permberton IK., Wuhrer M., Kolarich D., Fernandes DL., Theorodorou E., Victoria VM., Gardner RA., Doran R., Shubhakar A., Boyapati R., Rudan I., Lionetti P., Akmačić IT., Krištić J., Vuč ković F., Štambuk J., Novokmet M., Pučić-Baković M., Gornik O., Andriulli A., Cantoro L., Sturniolo G., Fiorino G., Manetti N., Latiano A., Kohn A., D'Inca‘ R., Danese S., Arnott ID., Noble CL., Lees CW., Shand AG., Ho GT., Murphy L., Gibson J., Evenden L., Wrobel N., Gilchrist T., Fawkes A., Kammeijer GSM., Clerc F., de Haan N., Vojta A., Samaržija I., Markulin D., Klasić M., Dobrinić P., Aulchenko Y., van den Heuve T., Jonkers D., Pierik M.
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