Human Genetics

, Volume 117, Issue 1, pp 16–26 | Cite as

Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma

  • Mitsuteru Akahoshi
  • Kazuhiko Obara
  • Tomomitsu Hirota
  • Akira Matsuda
  • Koichi Hasegawa
  • Naomi Takahashi
  • Makiko Shimizu
  • Kazuko Nakashima
  • Lei Cheng
  • Satoru Doi
  • Hiroshi Fujiwara
  • Akihiko Miyatake
  • Kimie Fujita
  • Noritaka Higashi
  • Masami Taniguchi
  • Tadao Enomoto
  • Xiao-Quan Mao
  • Hitoshi Nakashima
  • Chaker N. Adra
  • Yusuke Nakamura
  • Mayumi Tamari
  • Taro Shirakawa
Original Investigation

Abstract

Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control interferon-γ (IFN-γ) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter −1993T→C SNP, which is in linkage disequilibrium with a synonymous coding 390A→G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA; P=0.004, Pc=0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P=0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the −1993T→C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the −1993 position, resulting in increased transcriptional activity of the TBX21 gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-γ) production in human airways of individuals with the −1993T→C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.

Notes

Acknowledgements

This work was supported by grants-in-aid from the Ministry of Health, Labor, and Welfare, the Japan Science and Technology Corporation, and the Japanese Millennium project. We thank all participants in the study. We also thank Hiroshi Sekiguchi and Miki Kokubo for technical assistance and Chinatsu Fukushima for providing data on the patients.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Mitsuteru Akahoshi
    • 1
    • 2
  • Kazuhiko Obara
    • 1
    • 3
  • Tomomitsu Hirota
    • 1
  • Akira Matsuda
    • 1
  • Koichi Hasegawa
    • 4
  • Naomi Takahashi
    • 1
  • Makiko Shimizu
    • 1
  • Kazuko Nakashima
    • 1
    • 4
  • Lei Cheng
    • 4
  • Satoru Doi
    • 5
  • Hiroshi Fujiwara
    • 5
  • Akihiko Miyatake
    • 6
  • Kimie Fujita
    • 7
  • Noritaka Higashi
    • 8
  • Masami Taniguchi
    • 8
  • Tadao Enomoto
    • 9
  • Xiao-Quan Mao
    • 4
  • Hitoshi Nakashima
    • 2
  • Chaker N. Adra
    • 10
  • Yusuke Nakamura
    • 11
  • Mayumi Tamari
    • 1
  • Taro Shirakawa
    • 1
    • 4
  1. 1.Laboratory for Genetics of Allergic Diseases, SNP Research CenterRIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)YokohamaJapan
  2. 2.Department of Medicine and Biosystemic Science, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  3. 3.Hitachi ChemicalTokyoJapan
  4. 4.Department of Health Promotion and Human BehaviorKyoto University Graduate School of Public HealthKyotoJapan
  5. 5.Osaka Prefectural Medical Center for Respiratory and Allergic DiseasesOsakaJapan
  6. 6.Miyatake Asthma ClinicOsakaJapan
  7. 7.College of Nursing University of ShigaShigaJapan
  8. 8.Clinical Research CenterSagamihara National HospitalKanagawaJapan
  9. 9.Department of OtolaryngologyJapanese Red Cross Society, Wakayama Medical CenterWakayamaJapan
  10. 10.Department of MedicineBeth Israel Deaconess Medical CenterBostonUSA
  11. 11.Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical ScienceUniversity of TokyoTokyoJapan

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