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The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region.

ABSTRACT: The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cell types, we analyzed the methylome of the epithelial and immune cell populations of duodenal biopsies in CD patients and controls separately. We found a cell type-specific methylation signature that includes genes mapping to the HLA region, namely TAP1 and HLA-B. We also performed Immunochip SNP genotyping of the same samples and interrogated the expression of some of the affected genes. Our analysis revealed that the epithelial methylome is characterized by the loss of CpG island (CGI) boundaries, often associated to altered gene expression, and by the increased variability of the methylation across the samples. The overlap between differentially methylated positions (DMPs) and CD-associated SNPs or variants contributing to methylation quantitative trait loci (mQTLs) is minimal. In contrast, there is a notable enrichment of mQTLs among the most significant CD-associated SNPs. Our results support the notion that DNA methylation alterations constitute a genotype-independent event and confirm its role in the HLA region (apart from the well-known, DQ allele-specific effect). Finally, we find that a fraction of the CD-associated variants could exert its phenotypic effect through DNA methylation.

SUBMITTER: Fernandez-Jimenez N

PROVIDER: S-EPMC6362130 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region.

Fernandez-Jimenez Nora N Garcia-Etxebarria Koldo K Plaza-Izurieta Leticia L Romero-Garmendia Irati I Jauregi-Miguel Amaia A Legarda Maria M Ecsedi Szilvia S Castellanos-Rubio Ainara A Cahais Vincent V Cuenin Cyrille C Degli Esposti Davide D Irastorza Iñaki I Hernandez-Vargas Hector H Herceg Zdenko Z Bilbao Jose Ramon JR

Scientific reports 20190204 1

The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cel ...[more]

PMID: 30718669

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Project description:IntroductionHemorheology is the study of the flow properties of the blood and its elements, which, together with natural anticoagulants, are important determinants of cardiovascular events. This study aimed to assess hemorheological and natural anticoagulant profiles of patients with celiac disease (CeD) comprehensively.MethodsOur study is a case-control study (registered under ISRCTN49677481) comparing patients with CeD with age- and sex-matched control subjects (1:1). We measured erythrocyte deformability (ED) at high (3-30 Pa) and low shears (0.3-3 Pa), erythrocyte aggregation, whole blood viscosity, plasma viscosity, and natural anticoagulants (protein C, protein S, and antithrombin activity). Adherence to gluten-free diet was estimated through dietary interview and urine gluten immunogenic peptide (urine GIP) detection.ResultsAfter matching, we analyzed the data of 100 study participants. ED at high shears was impaired in CeD (P < 0.05 for all shears, confirmed by random forest analysis) independently of findings on CeD-specific serological assessment and urine GIP detection but slightly dependently on dietary adherence (P = 0.025 for 30 Pa shear). ED at low shears seemed to be impaired only in urine GIP+ CeD patients (P < 0.05 for all comparisons with urine GIP- CeD patients and control subjects). All parameters describing erythrocyte aggregation and whole blood viscosity were shifted toward a prothrombotic direction in patients with CeD with poor dietary adherence compared with those with good dietary adherence. Plasma viscosity and activity of natural anticoagulants did not differ across groups.DiscussionWe observed diet-dependent and diet-independent prothrombotic hemorheological alterations in CeD, which can contribute to the elevated cardiovascular risk. The untoward metabolic changes during gluten-free diet, which can further aggravate hemorheological status, may indicate the implementation of prevention strategies.(Equation is included in full-text article.).

Dataset Information

The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region.

Publications

The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region.

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