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

Abstract

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. We sought to perform an association study with these genes and asthma-related phenotypes in 3 independent Canadian familial asthma collections and 1 Australian asthma case-control study. 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. Uncorrected associations with polymorphisms within 7 genes were detected with 1 or more of the phenotypes in 1 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. 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.