Functional polymorphisms in the regulatory regions of the VNN1 gene are associated with susceptibility to inflammatory bowel diseases.

Abstract

BACKGROUND:

Vanin-1 is an epithelial pantetheinase, which regulates intestinal inflammation in mouse. We investigated whether human VNN1 levels could be associated to the susceptibility to inflammatory bowel diseases (IBD) and explored the participation of PPARg to these processes.

METHODS:

We studied VNN1 expression in colon biopsies from IBD patients. We investigated polymorphisms in the regulatory regions of the VNN1 gene and examined their genetic association with the disease. Functional relevance of these single-nucleotide polymorphisms (SNPs) was assayed, and we tested PPARg in nuclear complexes associated with specific VNN1 polymorphic sequences. In mouse, we examined Vanin-1 expression in gut and feces during dextran sulfate sodium-induced colitis and assayed the effect of PPARg on Vanin-1 regulation.

RESULTS:

VNN1 is expressed by enterocytes and is upregulated in IBD. Three SNPs are statistically associated to IBD. The regions containing these SNPs specifically bind nuclear complexes and are correlated with the VNN1 transcript abundance in colon in an allele-dependent manner. One rare SNP is associated to severe ulcerative colitis with strong VNN1 and dropped PPARg levels. PPARg is involved in nuclear complexes that bound to VNN1 regulatory sites. Similarly, Vanin-1 is tightly regulated in the mouse gut in normal and colitis conditions and PPARg regulates its expression.

CONCLUSIONS:

VNN1 is a marker for IBD. Polymorphic positions in the VNN1 locus are direct targets for nuclear factors that might regulate the level of VNN1 in colon, and this could be linked to IBD susceptibility. It is hoped that modulating locally VNN1 expression or activity can be exploited to develop future therapeutic strategies against IBD.

• Authors: Thomas Gensollen, Christophe Bourges, Pascal Rihet, Agathe Rostan, Virginie Millet, Tetsuro Noguchi, Violene Bourdon, Hagay Sobol, Laurent Dubuquoy, Benjamin Bertin, Maturin Fumery, Pierre Desreumaux, Jean-Frédéric Colombel, Mathias Chamaillard, Xavier Hebuterne, Paul Hofman, Philippe Naquet, Franck Galland
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 19 Issue 11 Pg. 2315-25 (Oct 2013) ISSN: 1536-4844 [Electronic] England
• PMID: 23949622 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• GPI-Linked Proteins
• RNA, Messenger
• Amidohydrolases
• pantetheinase

Topics

• Amidohydrolases (genetics, metabolism)
• Animals
• Blotting, Western
• Case-Control Studies
• Disease Susceptibility
• Electrophoretic Mobility Shift Assay
• Fluorescent Antibody Technique
• GPI-Linked Proteins (genetics, metabolism)
• Gastrointestinal Tract (metabolism, pathology)
• Humans
• Immunoenzyme Techniques
• Inflammatory Bowel Diseases (genetics, pathology)
• Mice
• Polymorphism, Single Nucleotide (genetics)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Regulatory Sequences, Nucleic Acid (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Array Analysis