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

Asthma and atopy show epidemiological association and are biologically link ed 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-4R alpha an d either gamma c or IL-13R alpha 1) and IL-13 operates through IL-13R (a he terodimer of IL-4R alpha and IL-13R alpha 1) to promote IgE synthesis and I gE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine-in promoting asthma, through the s timulation of bronchial epithelial mucus secretion and smooth muscle hyper- reactivity. We investigated the role of common genetic variants of IL-13 an d IL-13R alpha 1 in human asthma, considering IgE levels. A novel variant o f human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak o dds 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 promin ently expressed in bronchial epithelium and smooth muscle from asthmatic su bjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gin, is important in the internal constitution of the ligand and crucial in ligand-receptor i nteraction. A non-coding variant of IL-13R alpha 1, A1398G, on chromosome X q13, 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 ar e likely to be important promoters of human asthma; detailed functional ana lysis of their actions is needed.