Genetic variation in immune signaling genes differentially expressed in asthmatic lung tissues

Background: Eight genes in the immune signaling pathway shown to be differentially expressed in asthmatic lung biopsy specimens in a previous microarray experiment were selected as candidate genes for asthma susceptibility. Objective: We sought to perform an association study with these genes and asthma-related phenotypes in 3 independent Canadian familial asthma collections and I Australian asthma case-control study. Methods: Tagging single nucleotide polymorphisms were selected by using the HapMap public database (r(2) > 0.8; minor allele frequency >0.10) and genotyped with the Illumina platform. Family-based association and trend tests for asthma, atopy, airway hyperresponsiveness, and allergic asthma phenotypes were done in each sample, correcting for multiple testing. Results: Uncorrected associations with polymorphisms within 7 genes were detected with I or more of the phenotypes in I or more of the 4 populations (.001 < P <.05). After correction, the 15-lipoxygenase (15-LO) associations with airway hyperresponsiveness and allergic asthma remained significant in 2 Canadian samples (corrected P =.022 and .049, respectively) and the association of the CD14 antigen with asthma remained significant in 1 Canadian sample (corrected P =.042). In both cases a protective effect of the minor alleles was observed. Conclusion: Expression profiling studies are a useful way to identify candidate genes for asthma because this approach has led to the first report of an association with 15-LO in 2 independent populations. Because 15-LO is involved in anti-inflammatory processes, further functional and clinical investigation of the role of this biologic pathway in asthma is warranted.