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Potential celiac patients: a model of celiac disease pathogenesis.

ABSTRACT: BACKGROUND AND AIM: Potential celiacs have the 'celiac type' HLA, positive anti-transglutaminase antibodies but no damage at small intestinal mucosa. Only a minority of them develops mucosal lesion. More than 40 genes were associated to Celiac Disease (CD) but we still do not know how those pathways transform a genetically predisposed individual into an affected person. The aim of the study is to explore the genetic features of Potential CD individuals. METHODS: 127 'potential' CD patients entered the study because of positive anti-tissue transglutaminase and no mucosal lesions; about 30% of those followed for four years become frankly celiac. They were genotyped for 13 polymorphisms of 'candidate genes' and compared to controls and celiacs. Moreover, 60 biopsy specimens were used for expression studies. RESULTS: Potential CD bear a lighter HLA-related risk, compared to celiac (?(2)?=?48.42; p value?=?1×10(-8)). They share most of the polymorphisms of the celiacs, but the frequency of c-REL* G allele was suggestive for a difference compared to celiac (?(2)?=?5.42; p value?=?0.02). One marker of the KIAA1109/IL-2/IL-21 candidate region differentiated potentials from celiac (rs4374642: ?2?=?7.17, p value?=?0.01). The expression of IL-21 was completely suppressed in potentials compared to celiacs (p value?=?0.02) and to controls (p value?=?0.02), in contrast IL-2, KIAA1109 and c-REL expression were over-expressed. CONCLUSIONS: Potential CD show genetic features slightly different from celiacs. Genetic and expression markers help to differentiate this condition. Potential CD is a precious biological model of the pathways leading to the small intestinal mucosal damage in genetically predisposed individuals.

SUBMITTER: Sperandeo MP

PROVIDER: S-EPMC3132737 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Potential celiac patients: a model of celiac disease pathogenesis.

Sperandeo Maria Pia MP Tosco Antonella A Izzo Valentina V Tucci Francesca F Troncone Riccardo R Auricchio Renata R Romanos Jihane J Trynka Gosia G Auricchio Salvatore S Jabri Bana B Greco Luigi L

PloS one 20110708 7

<h4>Background and aim</h4>Potential celiacs have the 'celiac type' HLA, positive anti-transglutaminase antibodies but no damage at small intestinal mucosa. Only a minority of them develops mucosal lesion. More than 40 genes were associated to Celiac Disease (CD) but we still do not know how those pathways transform a genetically predisposed individual into an affected person. The aim of the study is to explore the genetic features of Potential CD individuals.<h4>Methods</h4>127 'potential' CD p ...[more]

PMID: 21760890

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Project description:BackgroundBlood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers.MethodsWe investigated the levels of messenger RNA (mRNA) in whole blood (n?=?49) and protein in plasma (n?=?22) from cases with active CD (n?=?20), with confirmed CD and normalized histology (n?=?15), and without a CD diagnosis (n?=?14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann-Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis.ResultsCXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-?B complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone.ConclusionsThe CD markers identified in this study further emphasize the significance of components related to NF-?B regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-?B interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD.

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Potential celiac patients: a model of celiac disease pathogenesis.

Publications

Potential celiac patients: a model of celiac disease pathogenesis.

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