Genetic analysis of asthma exacerbations.

ABSTRACT

BACKGROUND: Identifying genetic markers of susceptibility to exacerbations may improve patient management, decrease morbidity, and lead to drug development. OBJECTIVES: To assess whether genetic markers associated with severe asthma exacerbations in previous reports are associated with less severe events that do not require intensive care and intubation and to identify additional markers in candidate genes and throughout the genome. METHODS: A total of 199 patients and 502 controls (individuals without an exacerbation) were identified from 4 clinical trials. We genotyped 51 markers from 17 genes previously reported to be associated with exacerbations; a whole genome scan was used to identify additional markers. Admixture analysis was conducted to characterize the presence of ancestral groups. The genetic marker effects were assessed by logistic regression for each study followed by a meta-analysis. RESULTS: Several coding variants in the IL4R gene had a genetic effect across 3 studies, including rs1805011 in IL4R (P < .0006). In addition, 3 markers in the IFNB1 gene showed evidence of association (P < .002) but only in the study with African Americans. Because these markers did not meet the prespecified multiplicity-adjusted significance level of P = .0002, we were unable to confirm previously published results for less severe events. The whole genome scan identified genes related to mast cell mediator release. The admixture analysis suggests that ancestry was best characterized by the presence of 3 ancestral groups. CONCLUSION: We were unable to confirm previously reported associations of genetic markers with asthma exacerbations. Although, in general, the patients studied had less severe asthma than patients in earlier reports, these results suggest involvement of similar pathways. TRIAL REGISTRATION clinicaltrials.gov Identifiers NTC00452699, NCT00452348, NTC00102765, NCT00843193.