Journal Article

Genetic variants of IL-13 signalling and human asthma and atopy

A. Heinzmann, X.-Q. Mao, M. Akaiwa, R.T. Kreomer, P.-S. Gao, K. Ohshima, R. Umeshita, Y. Abe, S. Braun, T. Yamashita, M.H. Roberts, R. Sugimoto, K. Arima, Y. Arinobu, B. Yu, S. Kruse, T. Enomoto, Y. Dake, M. Kawai, S. Shimazu, S. Sasaki, C.N. Adra, M. Kitaichi, H. Inoue, K. Yamauchi, N. Tomichi, F. Kurimoto, N. Hamasaki, J.M. Hopkin, K. Izuhara, T. Shirakawa and K.A. Deichmann

in Human Molecular Genetics

Volume 9, issue 4, pages 549-559
Published in print March 2000 | ISSN: 0964-6906
Published online March 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.4.549
Genetic variants of IL-13 signalling and human asthma and atopy

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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-4Rα and either γc or IL-13Rα1) and IL-13 operates through IL-13R (a heterodimer of IL-4Rα and IL-13Rα1) 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-13Rα1 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-13Rα1, 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.

Journal Article.  6853 words.  Illustrated.

Subjects: Genetics and Genomics

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