MAGI2 Gene Region and Celiac Disease.

Amaia Jauregi-Miguel,Izortze Santin,Maialen Sebastian-Delacruz,Koldo Garcia-Etxebarria,Ainara Castellanos-Rubio,Irati Romero-Garmendia,Spanish Consortium For The Genetics Of Celiac Disease ,Ane Olazagoitia-Garmendia,Jose Ramón Bilbao,Iñaki Irastorza

doi:10.3389/fnut.2019.00187

Abstract

Celiac disease (CD) patients present a loss of intestinal barrier function due to structural alterations in the tight junction (TJ) network, the most apical unions between epithelial cells. The association of TJ-related gene variants points to an implication of this network in disease susceptibility. This work aims to characterize the functional implication of TJ-related, disease-associated loci in CD pathogenesis. We performed an association study of 8 TJ-related gene variants in a cohort of 270 CD and 91 non-CD controls. The expression level of transcripts located in the associated SNP region was analyzed by RT-PCR in several human tissues and in duodenal biopsies of celiac patients and non-CD controls. (si)RNA-driven silencing combined with gliadin in the Caco2 intestinal cell line was used to analyze the implication of transcripts from the associated region in the regulation of TJ genes. We replicated the association of rs6962966*A variant [p = 0.0029; OR = 1.88 (95%1.24–2.87)], located in an intron of TJ-related MAGI2 coding gene and upstream of RP4-587D13.2 transcript, bioinformatically classified as a long non-coding RNA (lncRNA). The expression of both genes is correlated and constitutively downregulated in CD intestine. Silencing of lncRNA decreases the levels of MAGI2 protein. At the same time, silencing of MAGI2 affects the expression of several TJ-related genes. The associated region is functionally altered in disease, probably affecting CD-related TJ genes.

Highlights

Celiac disease (CD) is a chronic enteropathy, characterized by villous atrophy and inflammation of the intestinal mucosa, that develops in genetically predisposed individuals
Polymorphisms in tight junction (TJ)-related genes MAGI2, PARD3, and MYO9B that potentially influence the homeostasis of the intestinal barrier have been associated with risk of gastrointestinal disorders like CD and Inflammatory bowel disease (IBD) [27, 29, 46]
The CD-associated allele has been proposed to be involved in MAGI2 gene function, but no studies have been performed to determine the possible effects of the CD-associated polymorphism

Summary

Introduction

Celiac disease (CD) is a chronic enteropathy, characterized by villous atrophy and inflammation of the intestinal mucosa, that develops in genetically predisposed individuals. The disease is caused by an inappropriate immune response to ingested gluten, a protein consisting of soluble gliadin and insoluble glutenin components that is found mostly in wheat, and in barley, rye and oat. There is evidence supporting that various environmental factors, such as repeated gastrointestinal infections [1, 2] or early infant feeding [3, 4] may contribute to triggering the disease. A lifelong gluten-free diet (GFD) is the only effective treatment for CD that achieves complete remission of the symptoms. CD is a complex genetic disorder, and multiple genes contribute to disease risk. Genome wide association (GWA) and follow-up genetic studies have identified several additional genomic regions associated to the disease, which probably contain CD susceptibility genes, but our understanding of the disease pathogenesis is still limited [5]

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