title: 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.
authors.affiliation: Department of Medicine, Division of Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario, Canada.
authors.forename: C C K
authors.initials: CC
authors.lastname: Hui
authors.affiliation: Department of Medicine, Division of Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Medicine, Division of Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Heroux
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, St Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Akhabir
authors.affiliation: Centre for Heart Lung Innovation, University of British Columbia, St Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Sandford
authors.affiliation: Firestone Institute for Respiratory Health, McMaster University, Hamilton, Ontario, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Neighbour
authors.affiliation: Department of Medicine, Division of Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario, Canada.
authors.forename: J A
authors.initials: JA
authors.lastname: Denburg
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012330:RNA, Double-Stranded / Q000494:pharmacology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D012330:RNA, Double-Stranded; D000094632:Thymic Stromal Lymphopoietin