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IL4R Mutations Are Associated with Asthma Exacerbations and Mast Cell/IgE Expression

¹ University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; ² Wake Forest University Health Sciences Center, Winston-Salem, North Carolina; ³ University of Wisconsin, Madison, Wisconsin; ⁴ University of Texas Medical Branch, Galveston, Texas; ⁵ Washington University School of Medicine, St. Louis, Missouri; ⁶ Imperial College London, London, United Kingdom; ⁷ Cleveland Clinic, Cleveland, Ohio; ⁸ University of Virginia, Charlottesville, Virginia; ⁹ Brigham and Women's Hospital, Boston, Massachusetts; ¹⁰ Emory University, Atlanta, Georgia; and ¹¹ National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Sally E. Wenzel, M.D., Pulmonary, Allergy, and Critical Care Medicine, NW 628 Montefiore, 3459 Fifth Avenue, Pittsburgh, PA 15213. E-mail: wenzelse{at}upmc.edu

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 (IL4R) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown.

Hypothesis: Allelic substitutions in IL4R 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. 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, 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.

Key Words: asthma • genetics • IL4R • exacerbations • mast cells • IgE

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Mutations in IL4R have previously been associated with asthma, airflow limitation, and receptor function. What This Study Adds to the Field Mutations in the IL4R gene are associated with asthma exacerbations and immunopathologic changes in the airways.

 

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