Neuropeptide s receptor 1 gene polymorphism is associated with susceptibility to inflammatory bowel disease.
OBJECTIVE
The neuropeptide S receptor (NPSR1) gene has been associated recently with asthma and maps in a region of chromosome 7 previously linked also to inflammatory bowel disease (IBD). NPSR1 is expressed on the epithelia of several organs including the intestine, and appears to be up-regulated in inflammation. We tested NPSR1 gene polymorphism for association with IBD and verified whether the expression of its 2 major isoforms (NPSR1-A and NPSR1-B) is altered in the intestine of IBD patients.


METHODS
Eight NPSR1 polymorphisms were genotyped in 2490 subjects from 3 cohorts of IBD patients and controls from Italy, Sweden, and Finland. Real-time polymerase chain reaction and immunohistochemistry were used to quantify NPSR1 messenger RNA (mRNA) and protein expression in intestinal biopsy specimens from IBD patients and controls.


RESULTS
Global analysis of the whole dataset identified strong association of a NPSR1 haplotype block with IBD (P = .0018) and its 2 major forms: Crohn's disease (CD) (P = .026) and ulcerative colitis (UC) (P = .003). Genetic effects caused by individual haplotypes were identified mainly for the predisposing haplotype H2 in CD (P = .0005) and the protective haplotype H8 in UC (P = .003). NPSR1 mRNA and protein levels were increased in IBD patients compared with controls, and the risk haplotype H2 correlated with higher expression of both NPSR1-A (P = .024) and NPSR1-B (P = .047) mRNAs.


CONCLUSIONS
NPSR1 polymorphism is associated with IBD susceptibility. Specific NPSR1 alleles might act as genetic risk factors for chronic inflammatory diseases of the epithelial barrier organs.
D'Amato
Mauro
M
Strategic Research Center IRIS, Karolinska Institutet, Stockholm, Sweden. mauro.damato@ki.se
Bruce
Sara
S
Bresso
Francesca
F
Zucchelli
Marco
M
Ezer
Sini
S
Pulkkinen
Ville
V
Lindgren
Cecilia
C
Astegiano
Marco
M
Rizzetto
Mario
M
Gionchetti
Paolo
P
Riegler
Gabriele
G
Sostegni
Raffaello
R
Daperno
Marco
M
D'Alfonso
Sandra
S
Momigliano-Richiardi
Patricia
P
Torkvist
Leif
L
Puolakkainen
Pauli
P
Lappalainen
Maarit
M
Paavola-Sakki
Paulina
P
Halme
Leena
L
Farkkila
Martti
M
Turunen
Ulla
U
Kontula
Kimmo
K
Lofberg
Robert
R
Pettersson
Sven
S
Kere
Juha
J
D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
C484532:NPSR1 protein, human; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled