Proteosomaalinen dysfunktio alkaa olla celiakiatutkimuksessa polttopisteessä

 https://allergenbureau.net/event/international-celiac-disease-symposium-2026/

A regulatory single nucleotide polymorphism in the ubiquitin D gene associated with celiac disease

• October 2009
• Human Immunology 71(1):96-9

DOI:10.1016/j.humimm.2009.09.359

• Source
• PubMed
  

  Abstract

  An aberrant immune response triggered by dietary gluten is the main driving force underlying celiac disease (CD), but other biologic pathways that are dysregulated also participate in disease development. Genetic variation within these pathways might influence expression, contributing to susceptibility to CD. We have investigated the implication of ubiquitin D (UBD), a member of the ubiquitin–proteasome system that is strongly upregulated in the intestinal mucosa of active CD. Reverse transcriptase-polymerase chain reaction analysis of intestinal biopsy sample pairs (at diagnosis vs treated) from 30 CD patients confirmed overexpression of UBD in active disease tissue (fold change = 8.3; p = 0.0022). In silico prediction tools identified rs11724 as a putative regulatory single nucleotide polymorphism and association analysis of 468 CD patients and 459 controls revealed that the minor rs11724*C allele was more frequent among patients (minor allele frequency = 0.44 vs 0.39; odds ratio [OR] = 1.23; p = 0.028) and suggested a dominant allele effect (OR = 1.49; p = 0.0045). Correlation of the rs11724 genotype and UBD mRNA levels (OR = 0.76; p = 0.0021) further supports its implication in disease development.
  Introduction

  Celiac disease (CD# OMIM 212750) is a chronic, immune-mediated enteropathy caused by intolerance to ingested gluten that develops in genetically susceptible individuals. It is one of the most common lifelong disorders affecting Caucasians. Recent studies have estimated a prevalence of CD close to 1:120 [1]. The major genetic determinant of CD maps to the human leukocyte antigen (HLA) class II region on the major histocompatibility complex (MHC) located on 6p21, and more than 90% of celiac patients carry at least one copy of the HLA-DQ2 heterodimer or, less frequently (∼6%), the HLA-DQ8 molecule. HLA alone has proven insufficient to explain all of the genetic susceptibility to CD [2] and much effort has been put into the discovery of additional susceptibility determinants in recent years, with numerous candidate gene association studies and several whole genome linkage analyses performed by different groups. The turnover of such strategies has been limited and results have very often been inconsistent across studies [3]. More recently, as a result of the Genome-Wide Association Study (GWAS), a handful of novel celiac risk variants that are moderately (odds ratio [OR] < 1.5) but robustly associated with CD have been identified and the majority of the associated single nucleotide polymorphisms (SNPs) are in the vicinity of immune response-related genes that could be functionally implicated in development of the disease. However, linkage disequilibrium association mapping is unable either to define the actual genes that are involved in disease susceptibility or to explain the way in which associated DNA polymorphisms may influence the function of these genes [4], [5], so that putative candidates around each association peak must be independently studied in detail before causative variants can be confirmed. An alternative to the GWAS strategy is to focus on genes and pathways that have been shown to be functionally disrupted in the affected tissue and perform association analyses in selected DNA variants that might explain the changes observed. We have previously employed a gene selection strategy combining expression profiling and results from linkage studies with limited success [6] and now focus on altered genes that are important in disease-related pathways to identify potential candidates.

  The ubiquitin–proteasome system is an important biologic route in CD because it plays a central role in the selective degradation of intracellular proteins, including those involved in antigen presentation, nuclear factor-κB (NF-κB)-mediated inflammatory processes, cell cycle regulation, and cytokine gene expression [7]. Results from our previous gliadin-challenged microarray experiments indicated an overall upregulation of the ubiquitin–proteasome system pathway in intestinal mucosa from active celiac patients [6], [8]. Among the genes in the pathway, the most pronounced overexpression was observed for ubiquitin D (UBD) (p value = 2.52 × 10−8, FDR = 0.0009, and fold change = 14.14), a protein that is particularly interesting because it behaves as a ubiquitin-like modifier for rapid degradation of substrate proteins through the proteasome [9]. In addition, UBD is a good CD susceptibility candidate because it participates in the activation of the NF-κB pathway and has been shown to cause apoptosis in a caspase-dependent manner [10], two key events in disease development and progression. Moreover, the gene is located in the extended MHC region, where evidence for the presence of additional minor CD susceptibility loci has accumulated [11]. The aim of the present study was to investigate the potential implication of UBD in the pathogenesis of CD.