A thymic stromal lymphopoietin polymorphism may provide protection from asthma by altering gene expression

BACKGROUND: Genome-wide association studies have identified associations of the single nucleotide polymorphism rs1837253 in the thymic stromal lymphopoietin (TSLP) gene with asthma, allergic disease and eosinophilia. The TSLP gene encodes two isoforms, long and short, and previous studies have indicated functional differences between these two isoforms. OBJECTIVE: We investigated the expression of these TSLP isoforms in response to a pro-inflammatory signal, and the role of the rs1837253 genotype in gene isoform regulation. METHODS: We cultured nasal epithelial cells of asthmatic and non-asthmatic subjects and evaluated poly(I:C)-induced TSLP protein secretion using multiplex protein assays and gene expression profiles of the TSLP isoforms, and related genes using real-time qPCR. We correlated these profiles with rs1837253 genotype. RESULTS: Asthmatic nasal epithelial cells exhibited increased TSLP protein secretion compared with nasal epithelial cells from healthy controls. The long TSLP isoform was more responsive to poly(I:C) stimulation. Additionally, the minor T allele of rs1837253 was less inducible than the major C allele, suggesting differential regulation; this may explain the "protective" effects of the T allele in asthma. CONCLUSION: Our results provide important insights into the differential regulation and function of TSLP isoforms, including the role of TSLP rs1837253 polymorphisms in allergic inflammatory processes. CLINICAL RELEVANCE: The key finding on the influence of TSLP genetic variation on disease expression/endotype could provide basis for investigation into targeted biologics for anti-TSLP therapies.