Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 175, Issue 6, Pages 570-576Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200607-909OC
Keywords
asthma; genetics; IL4R alpha; exacerbations; mast cells; IgE
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Funding
- NCRR NIH HHS [RR-00051] Funding Source: Medline
- NHLBI NIH HHS [HL-69130, HL-69174, U10 HL109164, HL-69116, HL-69170, R01 HL069167, HL-69149, HL-69349, HL-69167, HL-69155] Funding Source: Medline
- NIAID NIH HHS [AI-40600] Funding Source: Medline
- Medical Research Council [G0400503B] Funding Source: researchfish
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Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor alpha (IL4R alpha) are associated with lower lung function, higher IgE, and again in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. Hypothesis: Allelic substitutions in IL4R alpha are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4R alpha. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. Conclusions: SNPs in IL4R alpha, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
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