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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.

Interaction between Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in Asthma