The rare IL-13R105Q variant, strongly enhances IL-13 protein activity (HYP6P.268)

Because common genetic variants account for only a modest proportion of human complex disease risk, rare variants are currently under investigation as potential sources of phenotypic variance. Focusing on IL13, one of the most replicated asthma/allergy susceptibility genes, we sought to assess the contribution of rare coding variants to disease risk by coupling sequencing-based variant discovery with in vitro studies of protein activity. Sequencing of IL13 exons in DNA from 96 non-Hispanic White and 96 African American asthmatics identified a rare non-synonymous variant (rs140828306, minor allele frequency 1.6% in African Americans) in exon 4 that results in a non-conservative arginine (R) /glutamine (Q) substitution at amino acid position 105, immediately upstream of a conserved IL-13 receptor binding domain. For functional studies, recombinant WT IL-13 and IL-13R105Q were expressed in eukaryotic cells and quantified by ELISA adjusting for differential antibody recognition of the variant. IL-13R105Q was significantly more potent than WT IL-13 in inducing STAT6 phosphorylation (16-fold) and CD23 expression (5-fold) in human monocytes, and transcription of allergy-associated genes in primary human epithelial cells grown at an air-liquid interface (3-43-fold). Neither protein acted on human T cells. These results show that IL-13R105Q is a gain-of-function variant that is likely to significantly enhance IL-13-dependent events in vivo.