edoc

Interaction between Retinoid acid receptor-related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in asthma

Acevedo, Nathalie and Sääf, Annika and Söderhäll, Cilla and Melén, Erik and Mandelin, Jami and Pietras, Christina Orsmark and Ezer, Sini and Karisola, Piia and Vendelin, Johanna and Gennäs, Gustav Boije Af and Yli-Kauhaluoma, Jari and Alenius, Harri and von Mutius, Erika and Doekes, Gert and Braun-Fahrländer, Charlotte and Riedler, Josef and van Hage, Marianne and D'Amato, Mauro and Scheynius, Annika and Pershagen, Göran and Kere, Juha and Pulkkinen, Ville. (2013) Interaction between Retinoid acid receptor-related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in asthma. PloS one, Vol. 8, H. 4 , e60111.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/dok/A6124530

Downloads: Statistics Overview

Abstract

Retinoid acid receptor-related Orphan Receptor Alpha (RORA) was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs) in the vicinity of the asthma-associated SNP (rs11071559) and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1), has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children) and the European cross-sectional PARSIFAL study (1120 children). Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C) was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36-2.93, p = 0.0003 in BAMSE; and 1.61, 1.18-2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively), and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Former Units within Swiss TPH > Microbial Exposure & Childhood Allergies (Braun-Fahrländer)
UniBasel Contributors:Braun-Fahrländer, Charlotte
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Public Library of Science
ISSN:1932-6203
Note:Publication type according to Uni Basel Research Database: Journal article
Related URLs:
Identification Number:
Last Modified:16 Aug 2013 07:34
Deposited On:16 Aug 2013 07:30

Repository Staff Only: item control page