title: PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.
abstract: BACKGROUND
  Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF-kappaB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD.
  
  
  METHODS
  Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2-mediated activation of NF-kappaB.
  
  
  RESULTS
  The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval [CI] 1.34-2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44-0.90). The PepT1 variant encoded by the C allele (PepT1-Ser117) was associated with reduced signaling downstream of NOD2 (P < 0.0001 compared to Pept1-Asn117).
  
  
  CONCLUSIONS
  A functional polymorphism in the SLC15A1 gene might be of relevance to inflammation and antibacterial responses in IBD. Whether this polymorphism truly contributes to disease susceptibility needs to be further addressed, and should stimulate additional studies in other populations.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Zucchelli
authors.forename: Leif
authors.initials: L
authors.lastname: Torkvist
authors.forename: Francesca
authors.initials: F
authors.lastname: Bresso
authors.forename: Jonas
authors.initials: J
authors.lastname: Halfvarson
authors.forename: Anna
authors.initials: A
authors.lastname: Hellquist
authors.forename: Francesca
authors.initials: F
authors.lastname: Anedda
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Assadi
authors.forename: Gunnar B
authors.initials: GB
authors.lastname: Lindgren
authors.forename: Monika
authors.initials: M
authors.lastname: Svanfeldt
authors.forename: Martin
authors.initials: M
authors.lastname: Janson
authors.forename: Colin L
authors.initials: CL
authors.lastname: Noble
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.forename: Maarit
authors.initials: M
authors.lastname: Lappalainen
authors.forename: Paulina
authors.initials: P
authors.lastname: Paavola-Sakki
authors.forename: Leena
authors.initials: L
authors.lastname: Halme
authors.forename: Martti
authors.initials: M
authors.lastname: Färkkilä
authors.forename: Ulla
authors.initials: U
authors.lastname: Turunen
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Robert
authors.initials: R
authors.lastname: Löfberg
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D005387:Finland; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D000074011:Peptide Transporter 1; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013548:Sweden; D027981:Symporters / Q000235:genetics*
chemical_list: D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters