Genetics of Asthma Exacerbations: A Candidate Gene and Genome-Wide Association Study

Abstract

RationaleExacerbations are a major cause of asthma morbidity and account for a large proportion of asthma healthcare costs. Discovering genetic markers of susceptibility to exacerbations could result in more targeted interventions.MethodsUsing data from four clinical trials (ADA109055/ADA109057/ SFA103153/I13106870) 701 samples were analyzed to conduct a genome-wide association study (GWAS) and an analysis of 50 markers from 18 candidate genes. Exacerbation cases were defined as subjects requiring treatment with systemic corticosteroids, an emergency room visit, or hospitalization for acute asthma symptoms. Controls were subjects without exacerbations. Meta-analysis was used to combine logistic regression results across studies. Principal components derived from genome-wide genetic markers accounted for ancestral diversity.ResultsNo genetic markers from candidate gene or GWAS analyses met pre-specified significance criteria (2.0x10−4 and 4.1x10−8, respectively) for association with asthma exacerbations. However, results from two candidate genes merited additional consideration. Although the direction of effect differed among studies, correlated coding variants in the IL-4 receptor gene (IL4R), a gene previously associated with asthma exacerbations, had the lowest meta-p-values across three studies (p <0.005). A single genetic effect was detected for interferon β1 (IFNB1) with exacerbations in the study that recruited only African-Americans (p<0.002).ConclusionsWhile no genetic markers met the pre-specified statistical criteria, two genes of interest were identified. The IL4R results may support previous findings of association with the IL-4/IL-13 pathway. Similarly, IFNB1 findings in African-Americans are consistent with innate immunity pathways contributing to asthma exacerbation susceptibility. Further studies are required to understand exacerbation associations. RationaleExacerbations are a major cause of asthma morbidity and account for a large proportion of asthma healthcare costs. Discovering genetic markers of susceptibility to exacerbations could result in more targeted interventions. Exacerbations are a major cause of asthma morbidity and account for a large proportion of asthma healthcare costs. Discovering genetic markers of susceptibility to exacerbations could result in more targeted interventions. MethodsUsing data from four clinical trials (ADA109055/ADA109057/ SFA103153/I13106870) 701 samples were analyzed to conduct a genome-wide association study (GWAS) and an analysis of 50 markers from 18 candidate genes. Exacerbation cases were defined as subjects requiring treatment with systemic corticosteroids, an emergency room visit, or hospitalization for acute asthma symptoms. Controls were subjects without exacerbations. Meta-analysis was used to combine logistic regression results across studies. Principal components derived from genome-wide genetic markers accounted for ancestral diversity. Using data from four clinical trials (ADA109055/ADA109057/ SFA103153/I13106870) 701 samples were analyzed to conduct a genome-wide association study (GWAS) and an analysis of 50 markers from 18 candidate genes. Exacerbation cases were defined as subjects requiring treatment with systemic corticosteroids, an emergency room visit, or hospitalization for acute asthma symptoms. Controls were subjects without exacerbations. Meta-analysis was used to combine logistic regression results across studies. Principal components derived from genome-wide genetic markers accounted for ancestral diversity. ResultsNo genetic markers from candidate gene or GWAS analyses met pre-specified significance criteria (2.0x10−4 and 4.1x10−8, respectively) for association with asthma exacerbations. However, results from two candidate genes merited additional consideration. Although the direction of effect differed among studies, correlated coding variants in the IL-4 receptor gene (IL4R), a gene previously associated with asthma exacerbations, had the lowest meta-p-values across three studies (p <0.005). A single genetic effect was detected for interferon β1 (IFNB1) with exacerbations in the study that recruited only African-Americans (p<0.002). No genetic markers from candidate gene or GWAS analyses met pre-specified significance criteria (2.0x10−4 and 4.1x10−8, respectively) for association with asthma exacerbations. However, results from two candidate genes merited additional consideration. Although the direction of effect differed among studies, correlated coding variants in the IL-4 receptor gene (IL4R), a gene previously associated with asthma exacerbations, had the lowest meta-p-values across three studies (p <0.005). A single genetic effect was detected for interferon β1 (IFNB1) with exacerbations in the study that recruited only African-Americans (p<0.002). ConclusionsWhile no genetic markers met the pre-specified statistical criteria, two genes of interest were identified. The IL4R results may support previous findings of association with the IL-4/IL-13 pathway. Similarly, IFNB1 findings in African-Americans are consistent with innate immunity pathways contributing to asthma exacerbation susceptibility. Further studies are required to understand exacerbation associations. While no genetic markers met the pre-specified statistical criteria, two genes of interest were identified. The IL4R results may support previous findings of association with the IL-4/IL-13 pathway. Similarly, IFNB1 findings in African-Americans are consistent with innate immunity pathways contributing to asthma exacerbation susceptibility. Further studies are required to understand exacerbation associations.