Genetic association analysis of the functional c.714T>G polymorphism and mucosal expression of dectin-1 in inflammatory bowel disease.

Abstract

BACKGROUND:

Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes beta-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.714T>G) in DECTIN-1 results in a loss-of-function (p.Y238X) and impaired cytokine responses, including TNF-alpha, interleukin (IL)-1beta and IL-17 upon in vitro stimulation with Candida albicans or beta-glucan. The aim of the present study was to test the hypothesis that the DECTIN-1 c.714T>G (p.Y238X) polymorphism is associated with lower disease susceptibility or severity in IBD and to investigate the level of dectin-1 expression in inflamed and non-inflamed colon tissue of IBD patients.

METHODOLOGY:

Paraffin embedded tissue samples from non-inflamed and inflamed colon of IBD patients and from diverticulitis patients were immunohistochemically stained for dectin-1 and related to CD68 macrophage staining. Genomic DNA of IBD patients (778 patients with Crohn's disease and 759 patients with ulcerative colitis) and healthy controls (n = 772) was genotyped for the c.714T>G polymorphism and genotype-phenotype interactions were investigated.

PRINCIPAL FINDINGS:

Increased expression of dectin-1 was observed in actively inflamed colon tissue, as compared to non-inflamed tissue of the same patients. Also an increase in dectin-1 expression was apparent in diverticulitis tissue. No statistically significant difference in DECTIN-1 c.714T>G allele frequencies was observed between IBD patients and healthy controls. Furthermore, no differences in clinical characteristics could be observed related to DECTIN-1 genotype, neither alone, nor stratified for NOD2 genotype.

CONCLUSIONS:

Our data demonstrate that dectin-1 expression is elevated on macrophages, neutrophils, and other immune cells involved in the inflammatory reaction in IBD. The DECTIN-1 c.714T>G polymorphism however, is not a major susceptibility factor for developing IBD.

• Authors: Hilbert S de Vries, Theo S Plantinga, J Han van Krieken, Rinke Stienstra, Ad A van Bodegraven, Eleonora A M Festen, Rinse K Weersma, J Bart A Crusius, Ronald K Linskens, Leo A B Joosten, Mihai G Netea, Dirk J de Jong
• Journal: PloS one (PLoS One) Vol. 4 Issue 11 Pg. e7818 (Nov 12 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 19915667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon, Terminator
• Interleukin-1beta
• Lectins, C-Type
• Membrane Proteins
• NOD2 protein, human
• Nerve Tissue Proteins
• Nod2 Signaling Adaptor Protein
• Tumor Necrosis Factor-alpha
• dectin 1

Topics

• Adult
• Case-Control Studies
• Codon, Terminator
• Colon (pathology)
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Humans
• Inflammation
• Inflammatory Bowel Diseases (genetics, metabolism)
• Interleukin-1beta (metabolism)
• Lectins, C-Type
• Male
• Membrane Proteins (biosynthesis, genetics)
• Myeloid Cells (metabolism)
• Nerve Tissue Proteins (biosynthesis, genetics)
• Nod2 Signaling Adaptor Protein (genetics)
• Polymorphism, Genetic
• Tumor Necrosis Factor-alpha (metabolism)