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 NakamuraMayumi Tamari, Taro Shirakawa

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)16-26
Number of pages11
JournalHuman Genetics
Volume117
Issue number1
DOIs
Publication statusPublished - Jun 1 2005

Fingerprint

Aspirin Induced Asthma
Asthma
Single Nucleotide Polymorphism
Genes
Phenotype
Interferons
Linkage Disequilibrium
Nuclear Proteins
Nose
Protein Binding
Aspirin
Exons
Hypersensitivity
Transcription Factors
Chromosomes
Binding Sites
T-Lymphocytes
Antigens

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Akahoshi, M., Obara, K., Hirota, T., Matsuda, A., Hasegawa, K., Takahashi, N., ... Shirakawa, T. (2005). Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Human Genetics, 117(1), 16-26. https://doi.org/10.1007/s00439-005-1285-0

Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. / Akahoshi, Mitsuteru; Obara, Kazuhiko; Hirota, Tomomitsu; Matsuda, Akira; Hasegawa, Koichi; Takahashi, Naomi; Shimizu, Makiko; Nakashima, Kazuko; Cheng, Lei; Doi, Satoru; Fujiwara, Hiroshi; Miyatake, Akihiko; Fujita, Kimie; Higashi, Noritaka; Taniguchi, Masami; Enomoto, Tadao; Mao, Xiao Quan; Nakashima, Hitoshi; Adra, Chaker N.; Nakamura, Yusuke; Tamari, Mayumi; Shirakawa, Taro.

In: Human Genetics, Vol. 117, No. 1, 01.06.2005, p. 16-26.

Research output: Contribution to journalArticle

Akahoshi, M, Obara, K, Hirota, T, Matsuda, A, Hasegawa, K, Takahashi, N, Shimizu, M, Nakashima, K, Cheng, L, Doi, S, Fujiwara, H, Miyatake, A, Fujita, K, Higashi, N, Taniguchi, M, Enomoto, T, Mao, XQ, Nakashima, H, Adra, CN, Nakamura, Y, Tamari, M & Shirakawa, T 2005, 'Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma', Human Genetics, vol. 117, no. 1, pp. 16-26. https://doi.org/10.1007/s00439-005-1285-0
Akahoshi, Mitsuteru ; Obara, Kazuhiko ; Hirota, Tomomitsu ; Matsuda, Akira ; Hasegawa, Koichi ; Takahashi, Naomi ; Shimizu, Makiko ; Nakashima, Kazuko ; Cheng, Lei ; Doi, Satoru ; Fujiwara, Hiroshi ; Miyatake, Akihiko ; Fujita, Kimie ; Higashi, Noritaka ; Taniguchi, Masami ; Enomoto, Tadao ; Mao, Xiao Quan ; Nakashima, Hitoshi ; Adra, Chaker N. ; Nakamura, Yusuke ; Tamari, Mayumi ; Shirakawa, Taro. / Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. In: Human Genetics. 2005 ; Vol. 117, No. 1. pp. 16-26.
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AU - Akahoshi, Mitsuteru

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AU - Hirota, Tomomitsu

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AU - Hasegawa, Koichi

AU - Takahashi, Naomi

AU - Shimizu, Makiko

AU - Nakashima, Kazuko

AU - Cheng, Lei

AU - Doi, Satoru

AU - Fujiwara, Hiroshi

AU - Miyatake, Akihiko

AU - Fujita, Kimie

AU - Higashi, Noritaka

AU - Taniguchi, Masami

AU - Enomoto, Tadao

AU - Mao, Xiao Quan

AU - Nakashima, Hitoshi

AU - Adra, Chaker N.

AU - Nakamura, Yusuke

AU - Tamari, Mayumi

AU - Shirakawa, Taro

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