Neuropeptide s receptor 1 gene polymorphism is associated with susceptibility to inflammatory bowel disease.

Background& Aims: 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 (1111)). 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 1111) 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 1111) (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 1111) 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.