Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB

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  • Anders U. Eliasen
  • Casper Emil T. Pedersen
  • Ni Wang
  • Matteo Soverini
  • Amelie Fritz
  • Andréanne Morin
  • Jette Bork-Jensen
  • Preben B. Mortensen
  • David M. Hougaard
  • Jonas Bybjerg-Grauholm
  • Marie Bækvad-Hansen
  • Ole Mors
  • Anders D. Børglum
  • Esben Agerbo
  • Cilla Söderhall
  • Matthew C. Altman
  • Anna H. Thysen
  • Chris G. McKennan
  • James E. Gern
  • Carole Ober
  • Hans Bisgaard
  • Anders G. Pedersen

Background: Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. Objective: We sought to identify genetic interaction associated with the development of childhood asthma. Methods: We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. Results: We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. Conclusions: We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

TidsskriftJournal of Allergy and Clinical Immunology
Udgave nummer3
Sider (fra-til)622-630
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
All funding received by COPSAC is listed online at The Lundbeck Foundation (grant R16-A1694 ), the Ministry of Health (Denmark) (grant 903516), the Danish Council for Strategic Research (grant 0603-00280B ), and the Capital Region Research Foundation provided core support to the COPSAC research center . The iPSYCH project is funded by the Lundbeck Foundation (grants R102-A9118 and R155-2014-1724 ) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation . Support was also received from the US National Institutes of Health (grant HL129735 to H.B., K.B., and C.O.), the Lundbeck Foundation (grants R263-2017-3800 to A.U.E. and R163-2013-16235 to K.B.), and the Novo Nordisk Foundation (grant NNF18OC0031764 to K.B.) This research was conducted using data from the UK Biobank database (, project IDs 32683 and 54273.

Publisher Copyright:
© 2022 American Academy of Allergy, Asthma & Immunology

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