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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 ?(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 = 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.

SUBMITTER: Harada M 

PROVIDER: S-EPMC3159073 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.

Harada Michishige M   Hirota Tomomitsu T   Jodo Aya I AI   Hitomi Yuki Y   Sakashita Masafumi M   Tsunoda Tatsuhiko T   Miyagawa Takehiko T   Doi Satoru S   Kameda Makoto M   Fujita Kimie K   Miyatake Akihiko A   Enomoto Tadao T   Noguchi Emiko E   Masuko Hironori H   Sakamoto Tohru T   Hizawa Nobuyuki N   Suzuki Yoichi Y   Yoshihara Shigemi S   Adachi Mitsuru M   Ebisawa Motohiro M   Saito Hirohisa H   Matsumoto Kenji K   Nakajima Toshiharu T   Mathias Rasika A RA   Rafaels Nicholas N   Barnes Kathleen C KC   Himes Blanca E BE   Duan Qing Ling QL   Tantisira Kelan G KG   Weiss Scott T ST   Nakamura Yusuke Y   Ziegler Steven F SF   Tamari Mayumi M  

American journal of respiratory cell and molecular biology 20100723 6


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 epitheli  ...[more]

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