Genetic variants of IL-13 signalling and human asthma and atopy.
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.
Heinzmann
A
A
University Children's Hospital, University of Freiburg, Freiburg, Germany.
Mao
X Q
XQ
Akaiwa
M
M
Kreomer
R T
RT
Gao
P S
PS
Ohshima
K
K
Umeshita
R
R
Abe
Y
Y
Braun
S
S
Yamashita
T
T
Roberts
M H
MH
Sugimoto
R
R
Arima
K
K
Arinobu
Y
Y
Yu
B
B
Kruse
S
S
Enomoto
T
T
Dake
Y
Y
Kawai
M
M
Shimazu
S
S
Sasaki
S
S
Adra
C N
CN
Kitaichi
M
M
Inoue
H
H
Yamauchi
K
K
Tomichi
N
N
Kurimoto
F
F
Hamasaki
N
N
Hopkin
J M
JM
Izuhara
K
K
Shirakawa
T
T
Deichmann
K A
KA
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*
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