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-4Rα and either γc or IL-13Rα1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ra 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.
| Original language | English |
|---|---|
| Pages (from-to) | 549-559 |
| Number of pages | 11 |
| Journal | Human Molecular Genetics |
| Volume | 9 |
| Issue number | 4 |
| Publication status | Published - Mar 1 2000 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Genetics(clinical)
Cite this
Genetic variants of IL-13 signalling and human asthma and atopy. / Heinzmann, A.; Mao, X. Q.; Akaiwa, M.; Kreomer, R. T.; Gao, P. S.; Ohshima, K.; Umeshita, R.; Abe, Y.; Braun, S.; Yamashita, T.; Roberts, M. H.; Sugimoto, R.; Arima, K.; Arinobu, Y.; Yu, B.; Kruse, S.; Enomoto, T.; Dake, Y.; Kawai, M.; Shimazu, S.; Sasaki, S.; Adra, C. N.; Kitaichi, M.; Inoue, H.; Yamauchi, K.; Tomichi, N.; Kurimoto, F.; Hamasaki, N.; Hopkin, J. M.; Izuhara, K.; Shirakawa, T.; Deichmann, K. A.
In: Human Molecular Genetics, Vol. 9, No. 4, 01.03.2000, p. 549-559.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genetic variants of IL-13 signalling and human asthma and atopy
AU - Heinzmann, A.
AU - Mao, X. Q.
AU - Akaiwa, M.
AU - Kreomer, R. T.
AU - Gao, P. S.
AU - Ohshima, K.
AU - Umeshita, R.
AU - Abe, Y.
AU - Braun, S.
AU - Yamashita, T.
AU - Roberts, M. H.
AU - Sugimoto, R.
AU - Arima, K.
AU - Arinobu, Y.
AU - Yu, B.
AU - Kruse, S.
AU - Enomoto, T.
AU - Dake, Y.
AU - Kawai, M.
AU - Shimazu, S.
AU - Sasaki, S.
AU - Adra, C. N.
AU - Kitaichi, M.
AU - Inoue, H.
AU - Yamauchi, K.
AU - Tomichi, N.
AU - Kurimoto, F.
AU - Hamasaki, N.
AU - Hopkin, J. M.
AU - Izuhara, K.
AU - Shirakawa, T.
AU - Deichmann, K. A.
PY - 2000/3/1
Y1 - 2000/3/1
N2 - 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-4Rα and either γc or IL-13Rα1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ra 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.
AB - 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-4Rα and either γc or IL-13Rα1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ra 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.
UR - http://www.scopus.com/inward/record.url?scp=0034162827&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034162827&partnerID=8YFLogxK
M3 - Article
C2 - 10699178
AN - SCOPUS:0034162827
VL - 9
SP - 549
EP - 559
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 4
ER -