title: Interaction between retinoid acid receptor-related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma.
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.
authors.affiliation: Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Acevedo
authors.forename: Annika
authors.initials: A
authors.lastname: Sääf
authors.forename: Cilla
authors.initials: C
authors.lastname: Söderhäll
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.forename: Jami
authors.initials: J
authors.lastname: Mandelin
authors.forename: Christina Orsmark
authors.initials: CO
authors.lastname: Pietras
authors.forename: Sini
authors.initials: S
authors.lastname: Ezer
authors.forename: Piia
authors.initials: P
authors.lastname: Karisola
authors.forename: Johanna
authors.initials: J
authors.lastname: Vendelin
authors.forename: Gustav Boije af
authors.initials: GB
authors.lastname: Gennäs
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
authors.forename: Harri
authors.initials: H
authors.lastname: Alenius
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.forename: Gert
authors.initials: G
authors.lastname: Doekes
authors.forename: Charlotte
authors.initials: C
authors.lastname: Braun-Fahrländer
authors.forename: Josef
authors.initials: J
authors.lastname: Riedler
authors.forename: Marianne
authors.initials: M
authors.lastname: van Hage
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.forename: Annika
authors.initials: A
authors.lastname: Scheynius
authors.forename: Göran
authors.initials: G
authors.lastname: Pershagen
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Ville
authors.initials: V
authors.lastname: Pulkkinen
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D001249:Asthma / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D057906:Circadian Clocks / Q000235:genetics; D004843:Epistasis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics; D015810:Linkage Disequilibrium; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000494:pharmacology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: C484532:NPSR1 protein, human; D009479:Neuropeptides; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C506531:neuropeptide S, human
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