Genetic variants of IL-13 signalling and human asthma and atopy
Authors: Heinzmann, A.1; Mao, X.-Q.2; Akaiwa, M.3; Kreomer, R.T.4; Gao, P.-S.2; Ohshima, K.5; Umeshita, R.3; Abe, Y.3; Braun, S.1; Yamashita, T.6; Roberts, M.H.2; Sugimoto, R.3; Arima, K.3; Arinobu, Y.3; Yu, B.3; Kruse, S.7; Enomoto, T.8; Dake, Y.8; Kawai, M.9; Shimazu, S.10; Sasaki, S.11; Adra, C.N.12; Kitaichi, M.13; Inoue, H.14; Yamauchi, K.14; Tomichi, N.15; Kurimoto, F.6; Hamasaki, N.3; Hopkin, J.M.2; Izuhara, K.3; Shirakawa, T.2; Deichmann, K.A.1
Source: Human Molecular Genetics, Volume 9, Number 4, 1 March 2000 , pp. 549-559(11)
Publisher: Oxford University Press
- Free Content
- New Content
- Subscribed Content
- Free Trial Content
Abstract:
Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T<INF>h</INF>2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4R
and either 
c or IL-13R1) and IL-13 operates through IL-13R (a heterodimer of IL-4R and IL-13R1) 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-13R1 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-13R1, 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.
Document Type: Research article
Affiliations: 1: University Children’s Hospital, University of Freiburg, Freiburg, Germany, 10: Department of Paediatrics, National Wakayama Hospital, Wakayama, Japan, 11: Department of Paediatrics, Osaka Medical College, Takatsuki, Japan, 12: Departments of Medicine and Pathology, Division of Hematology/Oncology, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA, 13: Department of Laboratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan, 14: 3rd Department of Medicine, Iwate Medical University, Morioka, Japan and 15: Department of Pathology, Iwate Prefecture Central Hospital, Morioka, Japan 2: Experimental Medicine Unit, University of Wales Swansea, Swansea, UK, 3: Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 4: Department of Chemistry, Queen Mary Westfield College, University of London, London, UK, 5: Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan, 6: Mitsubishi-Kagaku BCL, Tokyo, Japan, 7: R&D Institute, UNITIKA Ltd, Uji, Japan, 8: Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Centre, Wakayama, Japan, 9: Kyoto Preventive Medical Centre, Kyoto, Japan,
- Free Content
- New Content
- Subscribed Content
- Free Trial Content
Click here for Page Help