title: Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants.
abstract: BACKGROUND
  IL-13 is a key mediator of allergic asthma. IL-13 mediates its effects via its receptor, a heterodimer composed of IL-4R alpha and IL-13R alpha1. Polymorphic variants of both IL-13 and IL-4R alpha have been shown to be associated with atopy.
  
  
  OBJECTIVE
  We examined the functional consequences of the Q110 IL-13 variant in vitro and in vivo to determine whether it displays enhanced functional activity compared with R110 IL-13, both in the context of I50Q551 IL-4R alpha and of the atopy-associated variant V50R551 IL-4R alpha.
  
  
  METHODS
  We used a mouse cell line stably expressing human IL-4R alpha and IL-13R alpha1 that readily responds to human IL-4 and IL-13. For in vivo analyses, we used BALB/c mice.
  
  
  RESULTS
  The Q110 IL-13 variant displayed significantly increased activity compared with R110 IL-13. Furthermore, mice treated with Q110 IL-13 variant displayed increased airways hyperresponsiveness relative to R110 IL-13. We then examined the functional consequences of Q110 IL-13 variant in combination with an atopy-associated variant of its receptor, IL-4R alpha (V50R551). Q110 IL-13 variant had increased activity on these cells as well, and, strikingly, the effect was greater than that observed in cells expressing I50Q551 IL-4R alpha.
  
  
  CONCLUSIONS
  Either Q110 IL-13 variant or V50R551 IL-4R alpha variant has enhanced function alone, but the 2 together have a synergistic effect on IL-13-dependent gene induction. Our data demonstrate the importance of relatively small individual differences in gene products from common single nucleotide polymorphisms that may result in larger combined differences. Furthermore, a relatively modest change in function from a single nucleotide polymorphism can result in an important biological difference in vivo.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Chen
authors.forename: Mark B
authors.initials: MB
authors.lastname: Ericksen
authors.forename: Linda S
authors.initials: LS
authors.lastname: Levin
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Khurana Hershey
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes; D002460:Cell Line; D014644:Genetic Variation; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D020641:Polymorphism, Single Nucleotide; D019948:Receptors, Interleukin-4 / Q000235:genetics*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D018793:Interleukin-13; D019948:Receptors, Interleukin-4