Nocturnal asthma is affected by genetic interactions between RORA and NPSR1.

Vincent D Gaertner, Sven Michel, John A Curtin, Ville Pulkkinen, Nathalie Acevedo, Cilla Söderhäll, Andrea von Berg, Albrecht Bufe, Otto Laub, Ernst Rietschel, Andrea Heinzmann, Burkhard Simma, Christian Vogelberg, Göran Pershagen, Erik Melén, Angela Simpson, Adnan Custovic, Juha Kere, Michael Kabesch

Journal: Pediatric pulmonology 2020;54(6):847-857

PMID: 30927345

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Abstract

BACKGROUND

Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes.

METHODS

Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N = 723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N = 1646).

RESULTS

RORA* NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth.

CONCLUSION

RORA* NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.

Address: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.; Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, and Manchester University NHS Foundation Trust, Manchester, UK.; Heart and Lung Center, Division of Pulmonary Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.; Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.; Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.; Department of Women´s and Children's Health, Karolinska Institutet, Stockholm, Sweden.; Children's Department, Research Institute for the Prevention of Allergic Diseases, Marien-Hospital, Wesel, Germany.; Department of Experimental Pneumology, Ruhr-University, Bochum, Germany.; Kinder- und Jugendarztpraxis Laub, Rosenheim, Germany.; Faculty of Medicine, University Children's Hospital, University of Cologne, Cologne, Germany.; Center for Pediatrics, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg im Breisgau, Germany.; Children's Department, University Teaching Hospital, Landeskrankenhaus Feldkirch, Feldkirch, Austria.; University Children's Hospital, Technical University Dresden, Dresden, Germany.; Institute of Environmental Medicine, Karolinska Institutet and Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.; Institute of Environmental Medicine, Karolinska Institutet and Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.; Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.; Department of Paediatrics, Imperial College, London, UK.; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.; Research Programs Unit, Program for Molecular Neurology, University of Helsinki, Folkhälsän Institute of Genetics, Helsinki, Finland.; Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.; School of Basic & Medical Biosciences, King's College London, London, England.

DOI: 10.1002/ppul.24292

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MeSH Terms: Adolescent, Asthma, Child, Circadian Rhythm, Cohort Studies, Cross-Sectional Studies, Databases, Genetic, Female, Genetic Predisposition to Disease, Humans, Hypersensitivity, Male, Nuclear Receptor Subfamily 1, Group F, Member 1, Phenotype, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, Risk Factors