title: Genetic variants of IL-13 signalling and human asthma and atopy.
abstract: Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.
authors.affiliation: University Children's Hospital, University of Freiburg, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinzmann
authors.forename: X Q
authors.initials: XQ
authors.lastname: Mao
authors.forename: M
authors.initials: M
authors.lastname: Akaiwa
authors.forename: R T
authors.initials: RT
authors.lastname: Kreomer
authors.forename: P S
authors.initials: PS
authors.lastname: Gao
authors.forename: K
authors.initials: K
authors.lastname: Ohshima
authors.forename: R
authors.initials: R
authors.lastname: Umeshita
authors.forename: Y
authors.initials: Y
authors.lastname: Abe
authors.forename: S
authors.initials: S
authors.lastname: Braun
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: M H
authors.initials: MH
authors.lastname: Roberts
authors.forename: R
authors.initials: R
authors.lastname: Sugimoto
authors.forename: K
authors.initials: K
authors.lastname: Arima
authors.forename: Y
authors.initials: Y
authors.lastname: Arinobu
authors.forename: B
authors.initials: B
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Kruse
authors.forename: T
authors.initials: T
authors.lastname: Enomoto
authors.forename: Y
authors.initials: Y
authors.lastname: Dake
authors.forename: M
authors.initials: M
authors.lastname: Kawai
authors.forename: S
authors.initials: S
authors.lastname: Shimazu
authors.forename: S
authors.initials: S
authors.lastname: Sasaki
authors.forename: C N
authors.initials: CN
authors.lastname: Adra
authors.forename: M
authors.initials: M
authors.lastname: Kitaichi
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Yamauchi
authors.forename: N
authors.initials: N
authors.lastname: Tomichi
authors.forename: F
authors.initials: F
authors.lastname: Kurimoto
authors.forename: N
authors.initials: N
authors.lastname: Hamasaki
authors.forename: J M
authors.initials: JM
authors.lastname: Hopkin
authors.forename: K
authors.initials: K
authors.lastname: Izuhara
authors.forename: T
authors.initials: T
authors.lastname: Shirakawa
authors.forename: K A
authors.initials: KA
authors.lastname: Deichmann
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001249:Asthma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001980:Bronchi / Q000737:chemistry / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D003198:Computer Simulation; D014644:Genetic Variation; D005973:Glutamine / Q000235:genetics; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000097:blood / Q000235:genetics* / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000235:genetics / Q000502:physiology; D008958:Models, Molecular; D018123:Receptors, Interleukin / Q000235:genetics; D053660:Receptors, Interleukin-13; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: C508181:IL13RA1 protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D005973:Glutamine; D015847:Interleukin-4