A multi-centre study of candidate genes for wheeze and allergy: the International Study of Asthma and Allergies in Childhood Phase 2

Genuneit J, Cantelmo JL, Weinmayr G, Wong GWK, Cooper PJ, Riikjärv MA, Gotua M, Kabesch M, von Mutius E, Forastiere F, Crane J, Nystad W, El Sharif N, Batllés-Garrido J, García-Marcos L, García-Hernández G, Morales Suárez-Varela MM, Nilsson L, Bråbäck L, Saraçlar Y, Weiland SK, Cookson WOC, Strachan DP, Moffatt MF, ISAAC Phase Two Study Group.

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.

Clin Exp Allergy 2009 Dec; 39(12): 1875-1888

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