Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma.

Nathalie Acevedo,Simon Kebede Merid,Vincent D Gaertner,Erik Melén,Michael Kabesch,Sini Ezer,Ville Pulkkinen,Mauro D’Amato,Cilla Söderhäll,Juha Kere,Yungling Leo Lee

doi:10.1371/journal.pone.0176568

Nathalie Acevedo, Simon Kebede Merid + Show 9 more

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https://doi.org/10.1371/journal.pone.0176568

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Abstract

Single nucleotide polymorphisms (SNPs) close to the gain-of-function substitution, Asn(107)Ile (rs324981, A>T), in Neuropeptide S Receptor 1 (NPSR1) have been associated with asthma. Furthermore, a functional SNP (rs4751440, G>C) in Neuropeptide S (NPS) encodes a Val(6)Leu substitution on the mature peptide that results in reduced bioactivity. We sought to examine the effects of different combinations of these NPS and NPSR1 variants on downstream signaling and genetic risk of asthma. In transfected cells, the magnitude of NPSR1-induced activation of cAMP/PKA signal transduction pathways and downstream gene expression was dependent on the combination of the NPS and NPSR1 variants with NPS-Val(6)/NPSR1-Ile(107) resulting in strongest and NPS-Leu(6)/NPSR1-Asn(107) in weakest effects, respectively. One or two copies of the NPS-Leu(6) (rs4751440) were associated with physician-diagnosed childhood asthma (OR: 0.67, 95%CI 0.49–0.92, p = 0.01) and together with two other linked NPS variants (rs1931704 and rs10830123) formed a protective haplotype (p = 0.008) in the Swedish birth cohort BAMSE (2033 children). NPS rs10830123 showed epistasis with NPSR1 rs324981 encoding Asn(107)Ile (p = 0.009) in BAMSE and with the linked NPSR1 rs17199659 (p = 0.005) in the German MAGIC/ISAAC II cohort (1454 children). In conclusion, NPS variants modify asthma risk and should be considered in genetic association studies of NPSR1 with asthma and other complex diseases.

Highlights

Neuropeptide S (NPS) affects multiple neuroendocrine, behavioral, and inflammatory responses via its G protein-coupled cell surface receptor NPSR1 (Neuropeptide S Receptor 1) [1,2,3,4]
NPSR1 was identified as a susceptibility gene for asthma and related traits by positional cloning and the associations of NPSR1 single nucleotide polymorphisms (SNPs) with asthma have been replicated in ethnically diverse populations [5,6,7,8,9,10,11,12], and marginally supported by a large-scale genome-wide association study (GWAS) [13]
To compare the bioactivities of the two NPS variants, we measured the dose-responses of NPSR1-Ile(107) and NPSR1-Asn(107) coding variants to either wildtype NPS-Val(6) or alternative NPS-Leu(6) in a luciferase assay dependent on the activation of a cAMP-response element (CRE)

Summary

Introduction

Neuropeptide S (NPS) affects multiple neuroendocrine, behavioral, and inflammatory responses via its G protein-coupled cell surface receptor NPSR1 (Neuropeptide S Receptor 1) [1,2,3,4]. The NPSR1 locus has shown allelic heterogeneity with different markers (tag SNPs, intronic markers, and haplotypes) showing associations depending on the study design and population being studied. We have previously shown that several susceptibility alleles of low-to-moderate-effects in NPSR1 may modify the asthma risk and show epistasis depending on the carrier status for variants in genes belonging to common biological pathways [17].

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