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

Michishige Harada, Tomomitsu Hirota, Aya I. Jodo, Yuki Hitomi, Masafumi Sakashita, Tatsuhiko Tsunoda, Takehiko Miyagawa, Satoru Doi, Makoto Kameda, Kimie Fujita, Akihiko Miyatake, Tadao Enomoto, Emiko Noguchi, Hironori Masuko, Tohru Sakamoto, Nobuyuki Hizawa, Yoichi Suzuki, Shigemi Yoshihara, Mitsuru Adachi, Motohiro EbisawaHirohisa Saito, Kenji Matsumoto, Toshiharu Nakajima, Rasika A. Mathias, Nicholas Rafaels, Kathleen C. Barnes, Blanca E. Himes, Qing Ling Duan, Kelan G. Tantisira, Scott T. Weiss, Yusuke Nakamura, Steven F. Ziegler, Mayumi Tamari

Research output: Contribution to journalArticlepeer-review

135 Citations (Scopus)

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 patientswith 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 β2-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.

Original languageEnglish
Pages (from-to)787-793
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume44
Issue number6
DOIs
Publication statusPublished - 2011 Jun 1

Keywords

  • Asthma
  • Bronchial epithelial cells
  • Combination therapy
  • Genetic polymorphisms
  • TSLP

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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