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Thorax 2010;65:124-131 doi:10.1136/thx.2009.119628
  • Asthma

Positionally cloned genes and age-specific effects in asthma and atopy: an international population-based cohort study (ECRHS)

  1. F Castro-Giner1,2,3,
  2. R de Cid3,4,
  3. J R Gonzalez1,2,3,
  4. D Jarvis5,
  5. J Heinrich6,
  6. C Janson7,
  7. E R Omenaas8,9,
  8. M C Matheson10,
  9. I Pin11,12,13,
  10. J M Antó1,2,3,14,
  11. M Wjst15,
  12. X Estivill3,4,14,
  13. M Kogevinas1,2,3,16
  1. 1Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
  2. 2Municipal Institute of Medical Research (IMIM-Hospital del Mar), Barcelona, Spain
  3. 3CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
  4. 4Genes and Disease Program, Center for Genomic Regulation, Barcelona, Spain
  5. 5Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College, London, UK
  6. 6Institute of Epidemiology, Helmholtz Zentrum München, Munich, Germany
  7. 7Department of Medical Sciences, Respiratory Medicine and Allergology, Uppsala University, Uppsala, Sweden
  8. 8Institute of Medicine, University of Bergen, Haukeland University Hospital, Bergen, Norway
  9. 9Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway
  10. 10Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Victoria, Australia
  11. 11Inserm, U823, Centre de Recherche Albert Bonniot, Immunobiologie et Immunothérapie des cancers, La Tronche, France
  12. 12University Joseph Fourier, Grenoble, France
  13. 13Centre Hospitalier Universitaire de Grenoble, Grenoble, France
  14. 14Department of Health and Experimental Sciences, University Pompeu Fabra, Barcelona, Spain
  15. 15German Research Center for Environmental Health, Helmholtz Centre GSF, Munich, Germany
  16. 16National School of Public Health, Athens, Greece
  1. Correspondence to Dr M Kogevinas, Centre for Research in Environmental Epidemiology, 88 Dr Aiguader Rd, Barcelona 08003, Spain; kogevinas{at}creal.cat
  • Received 15 May 2009
  • Accepted 29 October 2009
  • Published Online First 8 December 2009

Abstract

Background Several genes identified by positional cloning have been associated with asthma and atopy, but few findings have been replicated. Age at onset of asthma has been associated with different phenotypic characteristics, and with variants at chromosome 17q21 identified through genome-wide association. This study examined the associations and age-specific effects on asthma, atopy and bronchial hyper-responsiveness (BHR) of five candidate genes previously identified by positional cloning (ADAM33, PHF11, NPSR1, DPP10, SPINK5).

Methods 51 polymorphisms from 2474 participants from 13 countries who took part in the European Community Respiratory Health Survey (1990–2000) were studied. Asthma and age at onset of asthma were assessed by questionnaire data, BHR by methacholine challenge and atopy by specific immunoglobulin E to four common allergens.

Results Significant associations with asthma, atopy and particularly for asthma with atopy were observed for a large region of 47 kb in the NPSR1 gene, even after Bonferroni correction for multiple comparisons (p<0.001). The associations with NPSR1 were stronger in those reporting a first attack of asthma before the age of 15, with statistically significant interactions with age of onset found for three SNPs. The evidence for ADAM33 and BHR and for an age-specific effect of two SNPs in DPP10 and asthma was weaker.

Conclusion This study provides further evidence for an effect of NPSR1 on asthma, atopy and atopic asthma. In addition, this analysis suggests a role for NPSR1 in early-onset asthma driven by the strong effect of this gene on atopic asthma.

Footnotes

  • Additional data are published online only at http://thorax.bmj.com/content/vol65/issue2

  • Funding This work was supported by grants from the MaratoTV3, Catalonia, Spain and Genome Spain. Additional funding was available in each research centre for data collection.

  • Competing interests None.

  • Ethics approval Ethical approval was obtained for each centre from the appropriate institutional ethics committee and written consent was obtained from each participant.

  • ECRHS List of Principal Investigators and Senior Scientific Team (members of the ECRHS Steering Committee in italics): Australia: Melbourne (M Abramson, R Woods, E H Walters, F Thien, G Benke); France: Paris (F Neukirch, B Leynaert, R Liard, M Zureik), Grenoble (I Pin, J Ferran-Quentin); Germany: Erfurt (J Heinrich, M Wjst, C Frye, I Meyer); Norway: Bergen (A Gulsvik, E Omenaas, C Svanes, B Laerum); Spain: Barcelona (J M Antó, J Sunyer, M Kogevinas, J P Zock, X Basagana, A Jaen, F Burgos), Huelva (J Maldonado, A Pereira, J L Sanchez), Albacete (J Martinez-Moratalla Rovira, E Almar), Galdakao (N Muniozguren, I Urritia), Oviedo (F Payo); Sweden: Uppsala (C Janson, G Boman, D Norback, M Gunnbjornsdottir), Umea (E Norrman, M Soderberg, K Franklin, B Lundback, B Forsberg, L Nystrom); Switzerland: Basel (N Künzli, B Dibbert, M Hazenkamp, M Brutsche, U Ackermann-Liebrich); UK: London (P Burney, S Chinn, D Jarvis), Norwich (D Jarvis, B Harrison), Ipswich (D Jarvis, R Hall, D Seaton).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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