Multiple polymorphisms affect expression and function of the neuropeptide S receptor (NPSR1).

PLoS One 2011 21;6(12):e29523. Epub 2011 Dec 21.

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Background: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02).

Principal Findings: we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk.

Significance: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244468PMC
May 2012
5 Reads

Publication Analysis

Top Keywords

npsr1
9
receptor npsr1
8
npsr1 locus
8
expression function
8
expression gene
4
human leukocytes
4
luciferase expression
4
leukocytes detected
4
detected quantitative
4
levels human
4
mrna levels
4
gene reporter
4
assays npsr1
4
quantitative differences
4
npsr1 mrna
4
reporter assays
4
nps-induced genome-wide
4
associated three
4
activities associated
4
three npsr1
4

Similar Publications