First Degree Relatives of Patients with Celiac Disease Harbour an Intestinal Transcriptomic Signature that Might Protect them from Enterocyte Damage

Abstract

IntroductionCeliac disease (CeD) is an autoimmune enteropathy which affects approximately 0.7% of the global population. While first-degree relatives (FDR) of patients with CeD have a 7.5% risk of developing enteropathy, many remain protected. Therefore, intestinal mucosa of FDR might have protective compensatory mechanisms against immunological injury. We have explored the protective mechanisms that may be active in intestinal mucosa of FDR.MethodsIntestinal mucosal biopsies (4–5 pieces) from treatment naïve patients with CeD (n = 12), FDR (n = 12) (anti-tTG negative) and controls (n = 12) (anti-tTG negative) were obtained from each individual and subjected to microarray analysis using HT-12-v4 Human Expression BeadChips (Illumina). Differential gene expression analysis was carried out among CeD, FDR and controls; and resulting gene lists were analyzed using gene ontology and pathway enrichment tools.ResultsPatients with CeD, FDR and control groups displayed significant differential gene expression. Thirty seven genes were upregulated and 372 were downregulated in the intestinal mucosa of FDR in comparison to CeD and controls. Pseudogenes constituted about 18% (315/1751) of FDR differentially expressed genes, and formed “clusters” that associated uniquely with individual study groups. The three study groups segregated into distinct clusters in unsupervised (PCA) and supervised (random forests) modelling approaches. Pathways analysis revealed an emphasis on crypt-villous maintenance and immune regulation in the intestinal mucosa of FDR.ConclusionsOur analysis suggests that the intestinal mucosa of celiac FDR consist of a unique molecular phenotype that is distinct from CeD and controls. The transcriptomic landscape of FDR promotes maintenance of crypt-villous axis and modulation of immune mechanisms. These differences clearly demonstrate the existence of compensatory protective mechanisms in the FDR intestinal mucosa.

Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis

“…Using archived clinical FFPE duodenal biopsies and high-throughput transcriptome sequencing of celiac and control subjects we captured many of the previously described pathogenic pathways associated with celiac disease 9–12 , suggesting that our analysis is robust, and that using FFPE clinical samples is a valid approach. We provide evidence for host gene expression profiles driving lymphocyte activation and cytokine signaling in treatment naïve pediatric celiac disease.…”

“…To supplement recently published celiac disease mRNAseq transcriptomic studies 9,10 done on fresh frozen biopsies, and to improve our understanding of celiac pathogenesis, we applied a standardized high throughput mRNA sequencing (RNAseq) approach on FFPE archived duodenum biopsies used for clinical diagnosis of active pre-treatment celiac disease and controls subjects (n = 54). Our cohort represent the largest celiac disease mucosal transcriptomic cohort to date 9–12 (Table S1). We capture robust gene expression and pathways that are linked to celiac pathogenesis, which were validated independently in other cohorts 9,10 .…”

The pseudogenes of eukaryotic translation elongation factors (EEFs): Role in cancer and other human diseases

“…), oral squamous cell carcinoma, osteosarcoma (?) 73 , 74 , 75 EEF1A1P2 EEF1A1 pseudogene 2 14 14q31.1 1912 Bladder cancer (? ), Uterine cancer (?…”

A Systems Biology Approach to the Pathogenesis of Celiac Disease: Identification of Potential Protective and Promoting Mechanisms

“…The control group had a de nitive normal gastrointestinal on endoscopic examination, had normal crypt villous ratio, and were anti-tTG Ab negative. The original research article has full details about biopsy sampling and RNA extraction, microarray experiment, and hybridization of arrays (9).…”

“…It seems that compensatory protective mechanisms in healthy FDRs have prevented them from developing the disease. Comparing the molecular phenotype of patients and the healthy FDRs is important for determining protective and pathogenic mechanisms in disease progression (9).…”