Human Molecular Genetics Advance Access originally published online on February 27, 2008
Human Molecular Genetics 2008 17(11):1673-1682; doi:10.1093/hmg/ddn058
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Biological and genetic interaction between Tenascin C and Neuropeptide S receptor 1 in allergic diseases
1 Department of Biosciences and Nutrition 2 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 3 Astrid Lindgren Children's Hospital 4 Clinical Research Centre, Karolinska University Hospital, Stockholm, Sweden 5 Department of Medical Genetics 6 Department of Anatomy, University of Helsinki, Helsinki, Finland 7 Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland 8 Children's Hospital, Zurich University, Zurich, Switzerland 9 Children's hospital, Schwarzach, Austria 10 University Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany 11 University Utrecht, Institute for Risk Assessment Sciences, The Netherlands 12 Clinical Immunology and Allergy Unit 13 Clinical Allergy Research Unit, Department of Medicine Solna, Karolinska, Institutet and University Hospital, Stockholm, Sweden 14 Astra Zeneca R&D Mölndal, Mölndal, Sweden 15 Sachs Children's Hospital, Stockholm, Sweden
* To whom correspondence should be addressed at: Karolinska Institutet, Department of Biosciences and Nutrition, 14157 Huddinge, Sweden. Tel: +46 86089158; Fax: +46 87745538; Email: juha.kere{at}biosci.ki.se; juha.kere{at}helsinki.fi
Received December 3, 2007; Revised February 6, 2008; Accepted February 24, 2008
Neuropeptide S receptor 1 (NPSR1, GPRA 154, GPRA) has been verified as a susceptibility gene for asthma and related phenotypes. The ligand for NPSR1, Neuropeptide S (NPS), activates signalling through NPSR1 and microarray analysis has identified Tenascin C (TNC) as a target gene of NPS-NPSR1 signalling. TNC has previously been implicated as a risk gene for asthma. We aimed therefore to study the genetic association of TNC in asthma- and allergy-related disorders as well as the biological and genetic interactions between NPSR1 and TNC. Regulation of TNC was investigated using NPS stimulated NPSR1 transfected cells. We genotyped 12 TNC SNPs in the cross-sectional PARSIFAL study (3113 children) and performed single SNP association, haplotype association and TNC and NPSR1 gene–gene interaction analyses. Our experimental results show NPS-dependent upregulation of TNC-mRNA. The genotyping results indicate single SNP and haplotype associations for several SNPs in TNC with the most significant association to rhinoconjunctivitis for a haplotype, with a frequency of 29% in cases (P = 0.0005). In asthma and atopic sensitization significant gene–gene interactions were found between TNC and NPSR1 SNPs, indicating that depending on the NPSR1 genotype, TNC can be associated with either an increased or a decreased risk of disease. We conclude that variations in TNC modifies, not only risk for asthma, but also for rhinoconjunctivitis. Furthermore, we show epistasis based on both a direct suggested regulatory effect and a genetic interaction between NPSR1 and TNC. These results suggest merging of previously independent pathways of importance in the development of asthma- and allergy-related traits.
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