PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.
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.
Zucchelli
Marco
M
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Torkvist
Leif
L
Bresso
Francesca
F
Halfvarson
Jonas
J
Hellquist
Anna
A
Anedda
Francesca
F
Assadi
Ghazaleh
G
Lindgren
Gunnar B
GB
Svanfeldt
Monika
M
Janson
Martin
M
Noble
Colin L
CL
Pettersson
Sven
S
Lappalainen
Maarit
M
Paavola-Sakki
Paulina
P
Halme
Leena
L
Färkkilä
Martti
M
Turunen
Ulla
U
Satsangi
Jack
J
Kontula
Kimmo
K
Löfberg
Robert
R
Kere
Juha
J
D'Amato
Mauro
M
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*
D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters