Functional polymorphisms in the regulatory regions of the VNN1 gene are associated with susceptibility to inflammatory bowel diseases.
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.
1Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, Marseille, France; 2Institut National de la Santé et de la Recherche Médicale (Inserm), U1104, Marseille, France; 3Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France; 4Inserm, UMR_S1090, TAGC, Marseille, France; 5Aix-Marseille University, Marseille, France; 6Oncogenetic Laboratory, Institut Paoli Calmettes, Marseille, France; 7Université Lille Nord de France, Lille, France; 8Inserm U995, Lille, France; 9CHU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Claude, Huriez, Lille, France; 10UDSL, Faculte des Sciences Pharmaceutiques et Biologiques, Lille, France; 11Icahn School of Medicine at Mount Sinai, Mount Sinai, New York; 12Inserm U1080, IRCAN Team 3, Nice, France; 13Université de Nice Sophia Antipolis, Nice, France; and 14Human Tissue Biobank Centre de Ressources Biologiques INSERM, Pasteur Hospital, Nice, France.
Thomas
T
Gensollen
Christophe
C
Bourges
Pascal
P
Rihet
Agathe
A
Rostan
Virginie
V
Millet
Tetsuro
T
Noguchi
Violene
V
Bourdon
Hagay
H
Sobol
Laurent
L
Dubuquoy
Benjamin
B
Bertin
Maturin
M
Fumery
Pierre
P
Desreumaux
Jean-Frédéric
JF
Colombel
Mathias
M
Chamaillard
Xavier
X
Hebuterne
Paul
P
Hofman
Philippe
P
Naquet
Franck
F
Galland
D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D004198:Disease Susceptibility; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis
D058851:GPI-Linked Proteins; D012333:RNA, Messenger; D000581:Amidohydrolases; C022314:pantetheinase