Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.

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Aim To assess the pathobiological and translational importance of whole blood transcriptomic analysis in inflammatory bowel disease (IBD). Methods We analyzed whole blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn’s disease [CD, n = 156], ulcerative colitis [UC, n = 167], and controls [n = 267]), exploring differential expression (DESeq2), co-expression networks (WGCNA), and transcription factor involvement (EPEE, ChEA, DoRothEA). Findings were validated by analysis of an independent replication cohort (99 CD, 100 UC, and 95 controls). In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. Results Disease-specific transcriptomes were defined in IBD (8697 transcripts), CD (7152), and UC (8521), with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10 -118), MCEMP1 (LFC = 2.45, p = 7.37 × 10 -109), and S100A12 (LFC = 2.31, p = 2.15 × 10 -93). Significantly over-represented pathways included IL-1 (p = 1.58 × 10 -11), IL-4, and IL-13 (p = 8.96 × 10 -9). Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 (PU.1), CEBPB, and IRF2, all regulators of cytokine signaling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% CI 5.3–102.0). Conclusion Transcriptomic analysis has allowed for a detailed characterization of IBD pathobiology, with important potential translational implications.

The aim of the present study was to compare body fat mass (FM) and fat-free mass (FFM) estimates by bioelectric impedance spectroscopy (BIS), with respective estimates by dual-energy X-ray absorptiometry (DXA), in obese and non-obese subjects. Body composition was measured in ninety-three obese and non-obese men and women by BIS device, BodyScout (Fresenius Kabi, Bad Homburg, Germany) and DXA device, Lunar iDXA (GE Healthcare, Madison, WI, USA). Mean difference between the methods was analysed by t tests, and Bland-Altman plots were generated to further examine the differences between the methods. Mean difference between the estimates by DXA and BIS (D DXA2BIS and Bland -Altman 95 % limits of agreement) were as follows: FM 4·1 (2 2·9, 11·2) kg and 4·5 (2 2·9, 11·8) %, FFM 2 4·1 (2 11·2, 2·9) kg and 2 4·5 (211·9, 2·9) %, indicating large inter-individual variation and statistically significant underestimation of FM and overestimation of FFM by BIS, as compared to DXA. The underestimation of FMkg (FM measured in kg) and overestimation of FFMkg (FFM measured in kg) were more pronounced in men than in women, and the underestimation of FM% (FM measured in percent) and overestimation of FFM% (FFM measured in percent) were more pronounced in normal weight (BMI ¼ 20·0-24·9 kg/m 2 ) than in overweight and obese (BMI $25·0 kg/m 2 ) subjects. BIS may be suitable for classification of a population into groups according to FM and FFM. However, the large inter-individual variation suggests that this BIS device with the proprietary software is insufficient for estimation of single individual body FM and FFM.