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Chromosome 17q21 Gene Variants Are Associated with Asthma and Exacerbations but Not Atopy in Early Childhood

¹ Copenhagen Prospective Studies on Asthma in Childhood, The Danish Paediatrics Asthma Centre, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; ² Center for Applied Genomics and Division of Human Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ³ Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom

Correspondence and requests for reprints should be addressed to Hans Bisgaard, M.D., D.M.Sci, Copenhagen Studies on Asthma in Childhood, The Danish Paediatrics Asthma Centre, Faculty of Health Sciences, University of Copenhagen, Gentofte Hospital, Ledreborg Alle 34, DK-2900 Gentofte, Copenhagen, Denmark. E-mail: Bisgaard{at}copsac.dk

Rationale: An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups.

Objectives: To characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus.

Methods: The single nucleotide polymorphism (SNP), rs7216389, was genotyped in 376 of 411 children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort born to mothers with asthma together with 305 mothers and 224 fathers. Nineteen additional SNPs in the region were genotyped in the children. Investigator-diagnosed clinical endpoints were based on diary cards and clinic visits every 6 months and at acute symptoms from birth. Lung function, bronchial responsiveness, and sensitization were tested longitudinally from early infancy.

Measurements and Main Results: rs7216389 was significantly associated with the development of wheeze (hazard ratio 1.64 [1.05–2.59], P value = 0.03), asthma (hazard ratio, 1.88 [1.15–3.07], P = 0.01), and acute severe exacerbations (hazard ratio 2.66 [1.58–4.48], P value = 0.0002). The effect on wheeze and asthma was observed for early onset but not late onset of disease. The increased risk of exacerbations persisted from 1 to 6 years of age (incidence ratio 2.48 [1.42–4.32], P value = 0.001), and increased bronchial responsiveness was present in infancy and at 4 years of age, but not at 6 years. In contrast, rs7216389 conferred no risk of eczema, rhinitis, or allergic sensitization.

Conclusions: Variation at the chromosome 17q12-q21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.

Key Words: polymorphism • asthma • child • exacerbations • hyperresponsiveness • ORMDL3

AT A GLANCE COMMENTARY Scientific Knowledge on This Subject Chromosome 17q12-q21 is a well-replicated predisposition locus for childhood asthma. What This Study Adds to the Field Variation at the chromosome 17q12-21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.

 

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