TY - JOUR T1 - Interaction of retinoid acid receptor-related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma JF - European Respiratory Journal JO - Eur Respir J VL - 40 IS - Suppl 56 SP - 1865 AU - Ville Pulkkinen AU - Nathalie Acevedo AU - Cilla Söderhäll AU - Erik Melen AU - Christina Orsmark-Pietras AU - Sini Ezer AU - Jami Mandelin AU - Marianne van Hage AU - Annika Scheyenius AU - Göran Pershage AU - Juha Kere Y1 - 2012/09/01 UR - http://erj.ersjournals.com/content/40/Suppl_56/1865.abstract N2 - Rationale. Retinoid acid receptor-related orphan receptor alpha (RORA) was recently identified as a candidate gene for asthma by a genome-wide association study (Moffatt et al. NEJM 2010). To investigate whether RORA polymorphisms (SNPs) influence asthma susceptibility, we conducted a detailed genetic association study in the vicinity of the associated variant rs11071559. Furthermore, we hypothesized that RORA may have biological and genetic interactions with a previously implicated asthma gene, Neuropeptide S receptor 1 (NPSR1). Methods. We genotyped 37 RORA SNPs in the Swedish birth cohort BAMSE (2033 children) and the cross-sectional PARSIFAL study (1120 European children), and performed allele and genotype association and RORA-NPSR1 gene–gene interaction analyses. Regulation of RORA was investigated using NPSR1 over-expressing SH-SY5Y cells stimulated with NPS. Results. Seven RORA SNPs were associated with doctor-diagnosed childhood asthma. The allele T in rs7164773 was under-represented in cases in BAMSE (52.6% vs. 44.7%, [OR 0.72; 95%CI 0.60-0.87], p=0.0005). In PARSIFAL, the allele T of rs11071559 was under-represented in cases (13.6% vs. 8.5%, [OR 0.58; 95%CI 0.37-0.92], p=0.02). These associations were confirmed in the combined BAMSE and PARSIFAL material (p<0.005 and p<0.01, respectively). Significant gene-gene interactions influencing the asthma risk were found between RORA SNPs and NPSR1 SNPs. In cell line studies, NPS induced RORA mRNA expression. Conclusions. Genetic variations in RORA are associated with childhood asthma and show epistasis with NPSR1. A direct regulatory effect further suggests interaction of RORA and NPSR1 pathways. ER -