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

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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.

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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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Authors and Affiliations

  1. Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan

    Mitsuteru Akahoshi, Kazuhiko Obara, Tomomitsu Hirota, Akira Matsuda, Naomi Takahashi, Makiko Shimizu, Kazuko Nakashima, Mayumi Tamari & Taro Shirakawa

  2. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Mitsuteru Akahoshi & Hitoshi Nakashima

  3. Hitachi Chemical, Tokyo, Japan

    Kazuhiko Obara

  4. Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan

    Koichi Hasegawa, Kazuko Nakashima, Lei Cheng, Xiao-Quan Mao & Taro Shirakawa

  5. Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan

    Satoru Doi & Hiroshi Fujiwara

  6. Miyatake Asthma Clinic, Osaka, Japan

    Akihiko Miyatake

  7. College of Nursing, University of Shiga, Shiga, Japan

    Kimie Fujita

  8. Clinical Research Center, Sagamihara National Hospital, Kanagawa, Japan

    Noritaka Higashi & Masami Taniguchi

  9. Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan

    Tadao Enomoto

  10. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, USA

    Chaker N. Adra

  11. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yusuke Nakamura

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  1. Mitsuteru Akahoshi
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Correspondence to Mayumi Tamari.

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Akahoshi, M., Obara, K., Hirota, T. et al. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet 117, 16–26 (2005). https://doi.org/10.1007/s00439-005-1285-0

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