Human Molecular Genetics Advance Access published online on February 27, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn058
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Biological and genetic interaction between Tenascin C and Neuropeptide S receptor 1 in allergic diseases
1 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden 2 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 3 Astrid Lindgren Children's Hospital, Karolinska University Hospital, Sweden 4 Department of Medical Genetics, University of Helsinki, Helsinki, Finland 5 Department of Anatomy, University of Helsinki, Helsinki, Finland 6 Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland 7 Children's Hospital, Zurich University, Zurich, Switzerland 8 Children's hospital, Schwarzach, Austria 9 University Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany 10 University Utrecht, Institute for Risk Assessment Sciences, The Netherlands 11 Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden 12 Clinical Allergy Research Unit, Department of Medicine Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden 13 Astra Zeneca R&D Mölndal, Mölndal, Sweden 14 Clinical Research Centre, Karolinska University Hospital, Stockholm, Sweden 15 Sachs Children's Hospital, Stockholm, Sweden
* To whom correspondence should be addressed: Juha Kere, Karolinska Institutet, Department of Biosciences and Nutrition, 14157 Huddinge, Sweden. Tel: +46-8-6089158; Fax: +46-8-7745538; E-mail: juha.kere{at}biosci.ki.se
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 interaction 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 (3,113 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.