Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma

Abstract

Thymic stromal lymphopoietin (TSLP) triggers dendritic cell-mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter-reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting b 2 -agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P 5 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.Keywords: asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms Thymic stromal lymphoprotein (TSLP) is an epithelial cellderived cytokine that triggers dendritic cell-mediated T helper (Th) 2 inflammatory responses, and plays an important role in the initiation and maintenance of the allergic immune response (1-6). A recent study showed that TSLP is released by human epithelial cells in response to microbes, trauma, or inflammation, and potently activates mast cells (7). In humans, TSLP is highly expressed by airway epithelial cells during allergic inflammation (2), and the expression of the TSLP gene in asthmatic airways is correlated with both the expression of Th2-attracting chemokines and disease severity (3).Large numbers of association studies on asthma and asthmarelated phenotypes using genetic polymorphisms were performed in different populations (8). Recent studies showed roles of human genetic polymorphisms of the TSLP gene. A variant in TSLP was associated with reductions in IgE in response to cockroaches and total IgE in a sex-stratified analysis (9). A functional single-nucleotide polymorphism (SNP), rs3806933, was identified in the regulatory element of TSLP (10). The variant creates a binding site for a...

Asthma phenotypes and IgE responses

“…The combination of high-dose allergen exposure along with specific bacteria during the first year of life has been shown to induce a protective effect against atopy and wheezing [79]. The genetic susceptibility to allergen-induced Th2 responses [80,81] may also be explained partly by polymorphisms in the genes encoding IL-4, IL-4R, IL-13, TSLP and/or IL-33 [82][83][84][85]. Polymorphisms in the gene encoding ADAM (a disintegrin and metalloproteinase) 33 actually represent the most robust association not only with asthma and bronchial hyperreactivity, but also with immune-related traits of asthma such as the levels of total IgE and blood eosinophils [86,87].…”

Untangling asthma phenotypes and endotypes

“…TSLP gene expression also proved responsive to both ICS and LABA. The induction of TSLP mRNA and protein expression was synergistically impaired by a corticosteroid and salmeterol (77). A functional glucocorticoidinduced transcript 1 gene (GLCCI1) variant was associated with reduced lung function in response to ICS.…”

Exacerbation of Allergic Diseases by Chemicals: Role of TSLP

“…A single nucleotide polymorphism in the TSLP promoter region of the TSLP gene has been associated with bronchial asthma (14). Chromosome 5q22, which contains the TSLP gene, is a candidate locus of asthma (1) and eosinophilic esophagitis (EoE), which is characterized by the allergic-induced abnormal infiltration of eosinophils in the esophagus (1).…”