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.
Highlights
The Retinoic acid receptor-related Orphan Receptor Alpha (RORA; MIM 600825, chromosome 15q22.2) was recently implicated in asthma susceptibility by a genome-wide association study (GWAS) [1]
NPS stimulation increased the expression of RORA in SH-SY5Y cells over-expressing Neuropeptide S receptor 1 (NPSR1) in a time and dose dependent manner, and the effect could be partly inhibited by the selective antagonist of NPSR1, SHA 68 (N-[(4-fluorophenyl)methyl]tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide) (Figure 1a and File S1) [46]
The results obtained in the human embryonic kidney epithelial cell line (HEK293H cells) stably over-expressing NPSR1-A confirmed the dose-dependent regulation of RORA mRNA and related circadian clock genes 6 h after NPS stimulation (Figure 1b)
Summary
The Retinoic acid receptor-related Orphan Receptor Alpha (RORA; MIM 600825, chromosome 15q22.2) was recently implicated in asthma susceptibility by a genome-wide association study (GWAS) [1]. RORA is a transcription factor that belongs to the nuclear hormone-receptor superfamily (NR1) and binds as monomers to specific hormone response elements (RORE) in DNA. The asthma loci IL33, IL1RL1/IL18R1, RORA, and IL13 previously identified by GWAS belong to the same pathway, and could modify airway inflammation and interleukin responses that are crucial for the development of asthma [1,19]. A recent GWAS for lung function identified a SNP (rs1902618) within the intron 1 of RORA as a possible predictor of age-related decrease in forced expiratory volume in 1 second (FEV1) [21]
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