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Genetic variation in uncontrolled childhood asthma despite ICS treatment

The Pharmacogenomics Journal volume 16, pages 158–163 (2016)Cite this article

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Abstract

Genetic variation may partly explain asthma treatment response heterogeneity. We aimed to identify common and rare genetic variants associated with asthma that was not well controlled despite inhaled corticosteroid (ICS) treatment. Data of 110 children was collected in the Children Asthma Therapy Optimal trial. Associations of genetic variation with measures of lung function (FEV1%pred), airway hyperresponsiveness (AHR) to methacholine (Mch PD20) and treatment response outcomes were analyzed using the exome chip. The 17q12-21 locus (containing ORMDL3 and GSMDB) previously associated with childhood asthma was investigated separately. Single-nucleotide polymorphisms (SNPs) in the 17q12-21 locus were found nominally associated with the outcomes. The strongest association in this region was found for rs72821893 in KRT25 with FEV1%pred (P=3.75*10−5), Mch PD20 (P=0.00095) and Mch PD20-based treatment outcome (P=0.006). No novel single SNPs or burden tests were significantly associated with the outcomes. The 17q12-21 region was associated with FEV1%pred and AHR, and additionally with ICS treatment response.

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References

  1. O’Byrne PM, Pedersen S, Schatz M, Thoren A, Ekholm E, Carlsson L-G et al. The poorly explored impact of uncontrolled asthma. Chest 2013; 143: 511–523.

    Article  PubMed  Google Scholar 

  2. Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swiston J et al. Economic burden of asthma: a systematic review. BMC Pulm Med 2009; 9: 24.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31: 143–178.

    Article  CAS  PubMed  Google Scholar 

  4. Brannan JD . Bronchial hyperresponsiveness in the assessment of asthma control: Airway hyperresponsiveness in asthma: Its measurement and clinical significance. Chest 2010; 138: 11S–17S.

    Article  PubMed  Google Scholar 

  5. Tse SM, Tantisira K, Weiss ST . The pharmacogenetics and pharmacogenomics of asthma therapy. Pharmacogenomics J 2011; 11: 383–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007; 448: 470–473.

    Article  CAS  Google Scholar 

  7. Wan YI, Shrine NRG, Soler Artigas M, Wain LV, Blakey JD, Moffatt MF et al. Genome-wide association study to identify genetic determinants of severe asthma. Thorax 2012; 67: 762–768.

    Article  CAS  PubMed  Google Scholar 

  8. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010; 363: 1211–1221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet 2011; 43: 887–892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 2011; 365: 1173–1183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hindorff L, MacArthur J, Morales J, Junkins H, Hall P, Klemm A et al A Catalog of Published Genome-Wide Association Studies www.genome.gov/gwastudies.

  12. Exome chip design http://genome.sph.umich.edu/wiki/Exome_Chip_Design.

  13. Nuijsink M, Hop WCJ, Sterk PJ, Duiverman EJ, de Jongste JC . Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomised controlled trial. Eur Respir J 2007; 30: 457–466.

    Article  CAS  PubMed  Google Scholar 

  14. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC . Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl 1993; 16: 5–40.

    Article  CAS  PubMed  Google Scholar 

  15. Birnie D, Thoe Schwartzenberg GW, Hop WC, van Essen-Zandvliet EE, Kerrebijn KF . Does the outcome of the tidal breathing and dosimeter methods of assessing bronchial responsiveness in children with asthma depend on age? Thorax 1990; 45: 199–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Goldstein JI, Crenshaw A, Carey J, Grant GB, Maguire J, Fromer M et al. zCall: a rare variant caller for array-based genotyping: genetics and population analysis. Bioinformatics 2012; 28: 2543–2545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nature 2006; 38: 904–909.

    CAS  Google Scholar 

  18. Pinheiro J, Bates D, DebRoy S, Sarkar D, R Core Team. nlme: Linear and Nonlinear Mixed Effects Models 2012.

  19. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. R Development Core Team R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2012.

  21. Tang Z-Z, Lin D-Y . MASS: meta-analysis of score statistics for sequencing studies. Bioinformatics 2013; 29: 1803–1805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X . Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 2011; 89: 82–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN . A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol 2008; 121: 860–863.

    Article  CAS  PubMed  Google Scholar 

  24. Boomsma DI, Wijmenga C, Slagboom EP, Swertz MA, Karssen LC, Abdellaoui A et al. The Genome of the Netherlands: design, and project goals. Eur J Hum Genet 2013; 22: 221–227.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Okada Y, Hirota T, Kamatani Y, Takahashi A, Ohmiya H, Kumasaka N et al. Identification of nine novel loci associated with white blood cell subtypes in a Japanese population. PLoS Genet 2011; 7: e1002067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Imboden M, Bouzigon E, Curjuric I, Ramasamy A, Kumar A, Hancock DB et al. Genome-wide association study of lung function decline in adults with and without asthma. J Allergy Clin Immunol 2012; 129: 1218–1228.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Reddel HK, Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009; 180: 59–99.

    Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge Mariska Olivier for her technical support. The CATO study has been sponsored by GlaxoSmithKline.

Author information

Author notes

  1. G H Koppelman and A H Maitland-van der Zee: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    M Leusink, S J H Vijverberg, J A M Raaijmakers, A de Boer & A H Maitland-van der Zee

  2. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    M Leusink, N C Onland-Moret & P I W de Bakker

  3. Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands

    S J H Vijverberg & L Koenderman

  4. Department of Pediatric Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    J C de Jongste

  5. Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    P J Sterk

  6. Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    E J Duiverman & G H Koppelman

  7. Department of Pulmonology, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    D S Postma

  8. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    P I W de Bakker

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  1. M Leusink
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  10. A de Boer
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  13. A H Maitland-van der Zee
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Corresponding author

Correspondence to A H Maitland-van der Zee.

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Leusink, M., Vijverberg, S., Koenderman, L. et al. Genetic variation in uncontrolled childhood asthma despite ICS treatment. Pharmacogenomics J 16, 158–163 (2016). https://doi.org/10.1038/tpj.2015.36

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