Celiac disease: From genetics to epigenetics

Table 1 DNA methylation features in celiac disease

Predisposition to CeD	What	Result	Highlight in CeD
Allele-specific methylation (ASM)[24]		ASM in rs2762051 in DLEU1 gene	Linked to CeD phenotype
Rs906868 in LBH gene promoter[23]	Risk variant shared with RA	Disease-specific methylation	Different methylation in rs906868 can predispose to CeD or RA
			→ influence on Wnt signalling
Methylation in HLA region in CeD[30]	Specific patterns in epithelial and immune cells	Genotype-independent methylation (except for HLA-DPB2)	Methylation patterns in HLA region
			→ CeD predisposition
Methylation profiling in HLA-DQB1 and SLC17A3[32]	Bead-chip on saliva samples	Different methylation profiles, not confirmed in bigger cohort	Potential methylation-based screening
			Major validation needed
Opioid like-effect of gliadin[27]		Modulation of glutathione and DNA methylation	Predisposition to inflammation and oxidation
CeD pathogenesis
Methylation in NFkB-related genes[26]	NFkB pathway↑↑	Disruption of regulatory equilibrium	Co-methylation patterns typical of active CeD in NFkB pathway genes
Cell-specific methylation[30]		Epithelium → 43 DMP	Cell-specific methylation signature & gene expression in CeD vs controls
		Immune cells → 310 DMP
Different methylation of SB2H3, IL-21, cREL and TNFAIP3[31]	Epithelium and lamina propria - specificity	Correlation with pro-inflammatory(↑) and cell adhesion(↓) pathways	Methylation of SB2H3 → epithelium
			Methylation of IL21 → lamina propria
			Typical of CeD samples.
Tumor development
↑CpGs methylation[20]	Microsatellite instability	↓MLH1 expression	Typical in CeD-related small bowel adenocarcinoma
MLH1 deregulation[21]	APC gene hyper-methylation	Chromosomal aberrations/microsatellite instability	Defects in mismatch repair
			Typical in CeD-related small bowel adenocarcinomas
Microsatellite instability[22]	Typical CpGs methylator phenotype	Methylation profiling → phenotypical classification	Mesenchymal and immune phenotypes are common in CeD-related small bowel carcinoma

CeD: Celiac disease; ASM: Allele specific methylation; RA: Rheumatoid arthritis; DMP: Differentially methylated positions; CpGs: CpG islands.