title: Neuropeptide S receptor induces neuropeptide expression and associates with intermediate phenotypes of functional gastrointestinal disorders.
abstract: OBJECTIVE
  NPSR1, the receptor for neuropeptide S (NPS), is expressed by gastrointestinal (GI) enteroendocrine cells, and is involved in inflammation, anxiety, and nociception. NPSR1 polymorphisms are associated with asthma and inflammatory bowel disease. We aimed to determine whether NPS induces expression of GI neuropeptides; and to associate NPSR1 single nucleotide polymorphisms (SNPs) with symptom phenotype and GI functions in health and functional GI disorders (FGID).
  
  
  METHODS
  The effect of NPS on messenger RNA expression of neuropeptides was assessed using real-time polymerase chain reaction in NPSR1-tranfected HEK293 cells. Seventeen NPSR1 SNPs were successfully genotyped in 699 subjects from a regional cohort of 466 FGID patients and 233 healthy controls. Associations were sought using gender-adjusted regression analysis and false discovery rate correction.
  
  
  RESULTS
  NPS-NPSR1 signaling induced increased expression of cholecystokinin, vasoactive intestinal peptide, peptide YY, and somatostatin. There were no significant associations with phenotypes of FGID symptoms. There were several NPSR1 SNPs associated with individual motor or sensory functions; the associations of SNPs rs2609234, rs6972158, and rs1379928 with colonic transit rate remained significant after false discovery rate correction. The rs1379928 polymorphism was also associated with pain, gas, and urgency sensory ratings at 36 mm Hg distention, the level prespecified for formal testing. Associations with rectal sensory ratings were not significant after false discovery rate correction.
  
  
  CONCLUSIONS
  Expression of several neuropeptides is induced upon NPS-NPSR1 signaling; NPSR1 variants are associated with colonic transit in FGID. The role of the NPS system in FGID deserves further study.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. camilleri.michael@mayo.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.forename: Paula
authors.initials: P
authors.lastname: Carlson
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
authors.forename: Sanna
authors.initials: S
authors.lastname: McKinzie
authors.forename: Irene
authors.initials: I
authors.lastname: Busciglio
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.forename: Marco
authors.initials: M
authors.lastname: Zucchelli
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D002478:Cells, Cultured; D019858:Enteroendocrine Cells / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D009479:Neuropeptides / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C484532:NPSR1 protein, human; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled