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. 2019 Oct;10(10):e00083.
doi: 10.14309/ctg.0000000000000083.

Identification of Epigenetic Methylation Signatures With Clinical Value in Crohn's Disease

Inés Moret-Tatay  1 , Elena Cerrillo  1   2 , Esteban Sáez-González  1   2 , David Hervás  3 , Marisa Iborra  1   2 , Juan Sandoval  4 , Enrique Busó  5 , Luis Tortosa  1 , Pilar Nos  1   2 , Belén Beltrán  1   2
Affiliations

Identification of Epigenetic Methylation Signatures With Clinical Value in Crohn's Disease

Inés Moret-Tatay et al. Clin Transl Gastroenterol. 2019 Oct.

Abstract

Introduction: DNA methylation is an epigenetic mechanism that regulates gene expression and represents an important link between genotype, environment, and disease. It is a reversible and inheritable mechanism that could offer treatment targets. We aimed to assess the methylation changes on specific genes previously associated with Crohn's disease (CD) and to study their possible associations with the pathology.

Methods: We included 103 participants and grouped them into 2 cohorts (a first [n = 31] and a second validation [n = 72] cohort), with active CD (aCD) and inactive CD (iCD) and healthy participants (CTR). DNA was obtained from the peripheral blood and analyzed by the Agena platform. The selected genes were catalase (CAT), α-defensin 5 (DEFA5), FasR, FasL, tumor necrosis factor (TNF), TNFRSF1A, TNFRSF1B, PPA2, ABCB1, NOD2, PPARγ, and PKCζ. We used the elastic net algorithm and R software.

Results: We studied 240 CpGs. Sixteen CpGs showed differential methylation profiles among aCD, iCD, and CTR. We selected for validation those with the greatest differences: DEFA5 CpG_11; CpG_13; CAT CpG_31.32; TNF CpG_4, CpG_12; and ABCB1 CpG_21. Our results validated the genes DEFA5 (methylation gain) and TNF (methylation loss) with P values < 0.001. In both cases, the methylation level was maintained and did not change with CD activity (aCD vs iCD). The subanalysis comparison between aCD and iCD showed significant differential methylation profiles in other CpGs: TNF, FAS, ABCB1, CAT, and TNFRS1BF genes.

Discussion: The methylation status of DEFA5 and TNF genes provides a signature biomarker that characterizes patients with CD and supports the possible implication of the environment and the immune system in CD pathogenesis.

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Figures

Figure 1.
Figure 1.
Heatmap including the CpGs for discriminating control, active CD and inactive CD groups, showing statistically significant differences in the elastic net analysis. Rows (CpGs) and columns (patients) are ordered according to the results of hierarchical clustering. Color scale ranges from red for hypomethylation to green for hypermethylation. aCD, active (onset) CD; CD, Crohn's disease; CTR, healthy control subjects; iCD, inactive CD.
Figure 2.
Figure 2.
Heatmap including the CpGs for discriminating active CD and inactive CD groups, showing statistically significant differences in the random forest algorithm. Rows (CpGs) and columns (patients) are ordered according to the results of hierarchical clustering. Color scale ranges from red for hypomethylation to green for hypermethylation. aCD, active (onset) CD; CD, Crohn's disease; iCD, inactive CD.
Figure 3.
Figure 3.
Box plots displaying the distribution of β-values of the selected CpG for validation. aCD, active (onset) CD; CD, Crohn's disease; CTR, healthy control subjects; DEFA, defensin 5, iCD, inactive CD; TNF, tumour necrosis factor.
Figure 4.
Figure 4.
Box plots depicting the validation results for the selected CpG. aCD, active (onset) CD; CD, Crohn's disease; CTR, healthy control subjects; iCD, inactive CD; TNF, tumour necrosis factor.
See this image and copyright information in PMC

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