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Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn's Disease Patients.

ABSTRACT: Crohn's disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate the inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating monocytes by profiling their DNA methylome and relate it to the level of CD activity. We gathered an all-female age-matched cohort of 16 CD patients and 7 non-CD volunteers. CD patients were further subdivided into 8 CD patients with active disease (CD-active) and 8 CD patients in remission (CD-remissive) as determined by the physician global assessment. We identified 15 and 12 differentially methylated genes (DMGs) when comparing CD with non-CD and CD-active with CD-remissive, respectively. Differential methylation was predominantly found in the promoter regions of inflammatory genes. Comparing our observations with gene expression data on classical (CD14++CD16-), non-classical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes indicated that while 7 DMGs were differentially expressed across the 3 subsets, the remaining DMGs could not immediately be associated with differences in known populations. We conclude that CD activity is associated with differences in DNA methylation at the promoter region of inflammation-associated genes.

SUBMITTER: Li Yim AYF

PROVIDER: S-EPMC7230341 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn's Disease Patients.

Li Yim Andrew Y F AYF Duijvis Nicolette W NW Ghiboub Mohammed M Sharp Catriona C Ferrero Enrico E Mannens Marcel M A M MMAM D'Haens Geert R GR de Jonge Wouter J WJ Te Velde Anje A AA Henneman Peter P

Journal of clinical medicine 20200408 4

Crohn's disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate the inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating monocytes by profiling their DNA methylome and relate it to the level of CD activity. We gathered an all-female age-matched cohort of 16 CD patients an ...[more]

PMID: 32276386

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Project description:Background & aimsDNA 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.MethodsTOPPIC 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).ResultsCD 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]).ConclusionsWe 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.

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Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn's Disease Patients.

Publications

Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn's Disease Patients.

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