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

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-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.

Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus

“…We detected 31 SNPs in the 262 chromosomes sequenced (Figure 1), six of which are singletons. The only nonsynonymous substitution we detected was the 2043G4A transition, which results in the Arg130Gln substitution reported by Heinzmann et al 6 The global estimated values of p (0.0013) and of y s (0.0012) are very similar to each other and to estimates from other nuclear genes. 19 We observed 30 fixed nucleotide differences between humans and chimpanzee.…”

“…The frequency of the Arg130Gln SNP differs among continental regions (F CT ¼ 0.27, Figure 4). The derived Gln130 allele has consistently been shown to be associated with asthmarelated disorders and proximal phenotypes (IL-13 and IgE serum levels) in European and Japanese samples, 6,44 as well as with sowda (a hyper-reactive onchoceriasis) in populations from Ghana and Guinea. 13 Moreover, molecular modeling suggests that the Arg130Gln amino-acid substitution is functionally important because it affects the binding site of IL-13 with its receptor.…”

“…13 Moreover, molecular modeling suggests that the Arg130Gln amino-acid substitution is functionally important because it affects the binding site of IL-13 with its receptor. 6,45 Thus, the relatively high frequency of the Gln130 amino acid in non-Africans and the low frequency of this variant in Africans could have implications for differential susceptibility to disease in populations originating from these regions. The common À1111T allele in the promoter region has also been associated with asthma, high levels of serum IL-13 and IgE, as well as asthma-proximal phenotypes (bronchial hyper-responsiveness and skin-test responsiveness) in case-control studies with European populations.…”

“…4 The IL13 gene encompasses 2938 bp and includes four exons, 56 bp of 5 0 UTR and 828 bp of 3 0 UTR ( Figure 1). Previous studies [6][7][8][9][10][11] and single-nucleotide polymorphism (SNP) discovery initiatives such as the University of Washington-Fred Hutchinson Cancer Research Center Variation Discovery Resource (http://pga.gs.washington.edu/) and SNP500Cancer (http://snp500cancer.nci.-nih.gov/) have identified 32 SNPs in the IL13 gene and its promoter region in European, European-American, Chinese, Japanese, African American and African samples. These include two SNPs in the promoter region and a single nonsynonymous substitution (2043G4A, Arg130Gln), located in exon 4.…”

“…These include two SNPs in the promoter region and a single nonsynonymous substitution (2043G4A, Arg130Gln), located in exon 4. Epidemiological studies in different populations have shown an association of the À1111T allele in the promoter region, 8,9,12 or of the Gln130 allele, 6,7,12 with different asthma-related disorders and proximal risk phenotypes, such as serum IL-13 and IgE levels. Moreover, Hoerauf et al 13 have identified an association between the Gln130 allele and sowda, an immunological hyper-reactive form of onchocerciasis.…”