A multi-centre study of candidate genes for wheeze and allergy: the International Study of Asthma and Allergies in Childhood Phase 2.
BACKGROUND
Common polymorphisms have been identified in genes suspected to play a role in asthma. We investigated their associations with wheeze and allergy in a case-control sample from Phase 2 of the International Study of Asthma and Allergies in Childhood.


METHODS
We compared 1105 wheezing and 3137 non-wheezing children aged 8-12 years from 17 study centres in 13 countries. Genotyping of 55 candidate single nucleotide polymorphisms (SNPs) in 14 genes was performed using the Sequenom System. Logistic regression models were fitted separately for each centre and each SNP. A combined per allele odds ratio and measures of heterogeneity between centres were derived by random effects meta-analysis.


RESULTS
Significant associations with wheeze in the past year were detected in only four genes (IL4R, TLR4, MS4A2, TLR9, P<0.05), with per allele odds ratios generally <1.3. Variants in IL4R and TLR4 were also related to allergen-specific IgE, while polymorphisms in FCER1B (MS4A2) and TLR9 were not. There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE. Heterogeneity of effects across centres was rare, despite differences in allele frequencies.


CONCLUSIONS
Despite the biological plausibility of IgE-related mechanisms in asthma, very few of the tested candidates showed evidence of association with both wheeze and increased IgE levels. We were unable to confirm associations of the positional candidates DPP10 and PHF11 with wheeze, although our study had ample power to detect the expected associations of IL13 variants with IgE and SPINK5 variants with eczema.
Genuneit
J
J
Institute of Epidemiology, Ulm University, Ulm, Germany. jon.genuneit@uni-ulm.de
Cantelmo
J L
JL
Weinmayr
G
G
Wong
G W K
GW
Cooper
P J
PJ
Riikjärv
M-A
MA
Gotua
M
M
Kabesch
M
M
von Mutius
E
E
Forastiere
F
F
Crane
J
J
Nystad
W
W
El-Sharif
N
N
Batlles-Garrido
J
J
García-Marcos
L
L
García-Hernández
G
G
Morales-Suarez-Varela
M
M
Nilsson
L
L
Bråbäck
L
L
Saraçlar
Y
Y
Weiland
S K
SK
Cookson
W O C
WO
Strachan
D
D
Moffatt
M F
MF
D000485:Allergens / Q000276:immunology; D001208:Asia; D001249:Asthma / Q000235:genetics; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D004484:Ecuador; D004485:Eczema / Q000235:genetics; D005060:Europe; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D006967:Hypersensitivity / Q000097:blood / Q000235:genetics* / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D009520:New Zealand; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics; D017455:Receptors, IgE / Q000235:genetics; D012135:Respiratory Sounds / Q000235:genetics* / Q000276:immunology; D012221:Rhinitis, Allergic, Perennial / Q000235:genetics; D006255:Rhinitis, Allergic, Seasonal / Q000235:genetics; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D012882:Skin Tests; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000485:Allergens; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C504000:IL4R protein, human; D018793:Interleukin-13; D053662:Interleukin-4 Receptor alpha Subunit; D018950:Lipopolysaccharide Receptors; C502447:MS4A2 protein, human; C493258:PHF11 protein, human; D053491:Proteinase Inhibitory Proteins, Secretory; C482643:RCBTB1 protein, human; D017455:Receptors, IgE; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; C508960:TGFB1 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases