Human Molecular Genetics, 2000, Vol. 9, No. 4 549-559
© 2000 Oxford University Press
Genetic variants of IL-13 signalling and human asthma and atopy
1University Children’s Hospital, University of Freiburg, Freiburg, Germany, 2Experimental Medicine Unit, University of Wales Swansea, Swansea, UK, 3Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 4Department of Chemistry, Queen Mary Westfield College, University of London, London, UK, 5Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan, 6R&D Institute, UNITIKA Ltd, Uji, Japan, 7Mitsubishi-Kagaku BCL, Tokyo, Japan, 8Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Centre, Wakayama, Japan, 9Kyoto Preventive Medical Centre, Kyoto, Japan, 10Department of Paediatrics, National Wakayama Hospital, Wakayama, Japan, 11Department of Paediatrics, Osaka Medical College, Takatsuki, Japan, 12Departments of Medicine and Pathology, Division of Hematology/Oncology, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA, 13Department of Laboratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan, 143rd Department of Medicine, Iwate Medical University, Morioka, Japan and 15Department of Pathology, Iwate Prefecture Central Hospital, Morioka, Japan
Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (Th2) 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.
+ These authors contributed equally to this work
§ To whom correspondence should be addressed. T.S.—Tel: +44 1792 513046; Fax: +44 1792 513054; Email: t.shirakawa@swansea.ac.uk. K.A.D.—Tel: +49 761 270 6371; Fax: +49 761 270 6372; Email: deichmann@kkl200.ukl.uni-freiburg.de
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