Tachdjian, RaffiAl Khatib, ShadiBryce, Paul J.Kim, Hong S.Blaeser, FrankO'Connor, Brian D.Rzymkiewicz, DanutaHoltzman, Michael J.Hershey, Gurjit K.Garn, HolgerHarb, HaniChatila, Talal A.Mathias, Clinton B.Chen, AndrewRenz, HaraldOettgen, Hans2011-11-222009Tachdjian, Raffi, Clinton Mathias, Shadi Al Khatib, Paul J. Bryce, Hong S. Kim, Frank Blaeser, Brian D. O'Connor, et al. 2009. Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. The Journal of Experimental Medicine 206(10): 2191-2204.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:5350698Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling.en-USJournal Article2011-11-2210.1084/jem.20091480