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 journalArticlepeer-review

71 Citations (Scopus)


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
Issue number1
Publication statusPublished - Jun 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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