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Published ahead of print on December 14, 2006, doi:10.1164/rccm.200607-909OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 6, March 2007, 570-576

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Submitted on July 5, 2006
Accepted on December 14, 2006

IL-4R{alpha} Mutations are Associated with Asthma Exacerbations and Mast Cells/IgE Expression

Sally E Wenzel1*, Silvana Balzar1, Elizabeth Ampleford2, Gregory A Hawkins2, William W Busse3, William J Calhoun4, Mario Castro5, K. Fan Chung6, Serpil Erzurum7, Benjamin Gaston8, Elliot Israel9, W. Gerald Teague10, Douglas Curran-Everett11, Deborah A Meyers2, and Eugene R Bleecker2

1 University of Pittsburgh Medical Center, Pittsburgh, PA, United States, 2 Wake Forest University Health Sciences Center, Winston-Salem, NC, USA, 3 University of Wisconsin, Madison, WI, USA, 4 University of Texas Medical Branch, Gavelston, TX, USA, 5 Washington University School of Medicine, St. Louis, MO, USA, 6 Imperial College, London, United Kingdom, 7 Cleveland Clinic, Cleveland, OH, USA, 8 University of Virginia, Charlottesville, VA, USA, 9 Brigham and Women's Hospital, Boston, MA, USA, 10 Emory University, Atlanta, GA, USA, 11 National Jewish Medical and Research Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: wenzels{at}njc.org.

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 (IL-4R{alpha}) 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 IL-4R{alpha} will be associated with asthma exacerbations, lower lung function and tissue inflammation, in particular to mast cells and IgE. Methods. Two well characterized severe asthma cohorts were analyzed for 5 single nucleotide polymorphisms (SNP) in IL-4R{alpha}. These polymorphisms were compared to the history of severe asthma exacerbations and lung function. In the primary [National Jewish (NJ)] cohort, these polymorphisms were also compared to 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 NJ 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 Caucasians (the larger racial subgroup) were analyzed separately. Conclusions. SNPs in IL-4R{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.
Key words: asthma, genetics, IL-4R{alpha}, exacerbations, mast cells, IgE




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