Genetic variation in uncontrolled childhood asthma despite ICS treatment

M Leusink; S J H Vijverberg; L Koenderman; J A M Raaijmakers; J C de Jongste; P J Sterk; E J Duiverman; N C Onland-Moret; D S Postma; A de Boer; P I W de Bakker; G H Koppelman; A H Maitland-van der Zee

doi:10.1038/tpj.2015.36

Genetic variation in uncontrolled childhood asthma despite ICS treatment

Pharmacogenomics J. 2016 Apr;16(2):158-63. doi: 10.1038/tpj.2015.36. Epub 2015 May 12.

Authors

M Leusink^{1

2}, S J H Vijverberg^{1

3}, L Koenderman³, J A M Raaijmakers¹, J C de Jongste⁴, P J Sterk⁵, E J Duiverman⁶, N C Onland-Moret², D S Postma⁷, A de Boer¹, P I W de Bakker^{2

8}, G H Koppelman⁶, A H Maitland-van der Zee¹

Affiliations

¹ Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³ Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Department of Pediatric Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵ Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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.
⁷ Department of Pulmonology, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁸ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

PMID: 25963336
DOI: 10.1038/tpj.2015.36

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.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adrenal Cortex Hormones / therapeutic use*
Anti-Asthmatic Agents / therapeutic use*
Asthma / drug therapy
Asthma / genetics*
Asthma / physiopathology
Child
Chromosomes, Human, Pair 17 / genetics
Female
Genetic Association Studies
Genetic Loci
Humans
Male
Phenotype
Polymorphism, Single Nucleotide
Treatment Failure

Substances

Adrenal Cortex Hormones
Anti-Asthmatic Agents