Abstract
BackgroundBefore the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis.Methodology/Principal FindingsWe systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R.Conclusions/SignificanceOur results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.
Highlights
Asthma is a complex respiratory disease characterized by chronic inflammation of the airways and frequently associated with atopy, pulmonary obstruction and bronchial hyper-responsiveness against a diversity of stimulus [1]
A total of 75 Tagging SNPs (tSNPs), which maintained an adequate coverage for all genes (r2$0.85), and 211 imputed single nucleotide polymorphisms (SNPs) were considered for association studies in 1,865 samples (606 cases and 1,259 controls) (Table S3)
Association testing revealed a total of 35 SNPs (16 tSNPs and 19 imputed) that were associated with either asthma or atopic asthma at nominal significance, these were not considered significant in the context of the multiple comparisons (p-values .0.0012) (Table S3)
Summary
Asthma is a complex respiratory disease characterized by chronic inflammation of the airways and frequently associated with atopy, pulmonary obstruction and bronchial hyper-responsiveness against a diversity of stimulus [1]. Before the advent of genome-wide association studies (GWAS) [8], almost a thousand candidate-gene association studies for asthma and related traits were published [9]. Considering the gene as the unit of replication and using a broad definition for asthma, Ober & Hoffjan [5] elegantly summarized the accumulated evidence for candidate-gene association studies from the literature by assessing the consistency of findings [10]. Before the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. We aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis
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