title: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.affiliation: Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Hilbert S
authors.initials: HS
authors.lastname: de Vries
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: J Han
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Ad A
authors.initials: AA
authors.lastname: van Bodegraven
authors.forename: Eleonora A M
authors.initials: EA
authors.lastname: Festen
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: J Bart A
authors.initials: JB
authors.lastname: Crusius
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Linskens
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: de Jong
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D018388:Codon, Terminator; D003106:Colon / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D037181:Lectins, C-Type; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics*; D022423:Myeloid Cells / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D018388:Codon, Terminator; D053583:Interleukin-1beta; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha; D000099181:Dectin-1; C429018:NOD2 protein, human