Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood.
BACKGROUND
An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups.


OBJECTIVE
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.


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.
Bisgaard
Hans
H
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. Bisgaard@copsac.dk
Bønnelykke
Klaus
K
Sleiman
Patrick M A
PM
Brasholt
Martin
M
Chawes
Bo
B
Kreiner-Møller
Eskil
E
Stage
Malene
M
Kim
Cecilia
C
Tavendale
Roger
R
Baty
Florent
F
Pipper
Christian Bressen
CB
Palmer
Colin N A
CN
Hakonarsson
Hakon
H
D000403:Airway Resistance / Q000502:physiology; D001249:Asthma / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D005540:Forced Expiratory Flow Rates; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008176:Lung Volume Measurements; D008297:Male; D010092:Oximetry; D010641:Phenotype; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors