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

Hum Genet. 2005 Jun;117(1):16-26. doi: 10.1007/s00439-005-1285-0. Epub 2005 Apr 2.


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-gamma (IFN-gamma) 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, P(c) = 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-gamma) production in human airways of individuals with the -1993T-->C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / immunology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Aspirin / adverse effects*
  • Aspirin / immunology
  • Aspirin / therapeutic use
  • Asthma / chemically induced*
  • Asthma / genetics*
  • Binding Sites
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 17
  • Drug Hypersensitivity / genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Interferon-gamma / immunology
  • Japan
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic / genetics
  • Risk Factors
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / immunology
  • Th2 Cells / immunology
  • Transcription Factors / immunology
  • Transcription, Genetic


  • Anti-Inflammatory Agents, Non-Steroidal
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • Interferon-gamma
  • Aspirin