Thymic stromal lymphopoietin (TSLP) secretion from human nasal epithelium is a function of TSLP genotype

Abstract

Recent candidate gene and genome-wide association studies have identified "protective" associations between the single-nucleotide polymorphism (SNP) rs1837253 in the TSLP gene and risk for allergy, asthma, and airway hyperresponsiveness. The absence of linkage disequilibrium of rs1837253 with other SNPs in the region suggests it is likely a causal polymorphism for these associations, having functional consequences. We hypothesized that rs1837253 genotype would influence TSLP secretion from mucosal surfaces. We therefore evaluated the secretion of TSLP protein from primary nasal epithelial cells (NECs) of atopic and nonatopic individuals and its association with rs1837253 genotype. We found that although atopic sensitization does not affect the secretion of TSLP from NECs, there was decreased TSLP secretion in NECs obtained from heterozygous (CT; 1.8-fold) and homozygous minor allele (TT; 2.5-fold) individuals, as compared with NECs from homozygous major allele individuals (CC; P<0.05), after double-stranded RNA (dsRNA) stimulation (50 μg ml(-1)). Our novel results show that rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion. This may help explain the protective association of this genetic variant with asthma and related traits. Identifying functional consequences of SNPs in genes with previously reported clinical associations is critical in understanding and targeting allergic inflammation.

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

“…This indicates that the T allele is associated with decreased production of TSLP protein. Additionally, TSLP protein was decreased in non‐asthmatic individuals compared with asthmatic subjects, reinforcing the existing literature about the involvement of TSLP in asthma development . Our protein assay was not designed to detect the different isoforms of TSLP; validation at the protein level of our gene expression results, which showed differences between the short and long isoform of TSLP, is warranted.…”

“…NECs were expanded and cultured as previously described by Muller et al with some modifications. Poly(I:C) stimulation was performed as previously described by Hui et al RNA was extracted from the NECs using RNeasy Mini Kit (Qiagen) according to the manufacturer's instructions. The samples were reverse‐transcribed using iScript cDNA synthesis kit (Bio‐Rad) according to the manufacturer's instructions, and complementary DNA samples were aliquoted and stored at −80°C TSLP gene expression was assessed using SsoAdvanced™ Universal® SYBR Green Supermix (Bio‐Rad) with a MX4000 Stratagene detection system according to the manufacturer's instructions.…”

“…A single nucleotide polymorphism (SNP) rs1837253 in the upstream region of TSLP has been shown to be highly associated with asthma; multiple genome‐wide association studies (GWAS), including meta‐analyses spanning several ethnic groups, have confirmed and extended these associations to several asthma phenotypes (such as the eosinophilic endotype). The rs1837253 T allele (minor allele) is associated with a lower risk of asthma and hence considered to have a “protective” effect on asthma development . The TSLP gene encodes two transcript variants in humans: a long TSLP isoform (lfTSLP) and a short TSLP isoform (sfTSLP) .…”

“…The rs1837253 T allele (minor allele) is associated with a lower risk of asthma and hence considered to have a "protective" effect on asthma development. 13,20,21 The TSLP gene encodes two transcript variants in humans: a long TSLP isoform (lfTSLP) and a short TSLP isoform (sfTSLP). 22 The C terminal of the long isoform, common to both isoforms, 2 can be used to evaluate total TSLP transcripts.…”

Association of IL1RL1 rs3771180 and TSLP rs1837253 variants with asthma in the Guangxi Zhuang population in China

“…In Brazilians, the A allele of IL1RL1 rs1041973 was positively associated with IL‐5 production and Ig E levels; expression quantitative trait loci analysis also suggested that polymorphism regulated the expression of the IL1RL1 gene via amino acid substitution . TSLP SNP rs1837253 showed correlation with TSLP protein secretion in human nasal epithelium but not with TSLP mRNA levels . In recent years, a new technology called Hi‐C has been widely applied by researchers worldwide to reveal various epigenomic mechanisms of various diseases.…”