Original Investigation

Human Genetics

, Volume 117, Issue 1, pp 16-26

First online:

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

  • Mitsuteru AkahoshiAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University
  • , Kazuhiko ObaraAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)Hitachi Chemical
  • , Tomomitsu HirotaAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)
  • , Akira MatsudaAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)
  • , Koichi HasegawaAffiliated withDepartment of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health
  • , Naomi TakahashiAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)
  • , Makiko ShimizuAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)
  • , Kazuko NakashimaAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health
  • , Lei ChengAffiliated withDepartment of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health
    • , Satoru DoiAffiliated withOsaka Prefectural Medical Center for Respiratory and Allergic Diseases
    • , Hiroshi FujiwaraAffiliated withOsaka Prefectural Medical Center for Respiratory and Allergic Diseases
    • , Akihiko MiyatakeAffiliated withMiyatake Asthma Clinic
    • , Kimie FujitaAffiliated withCollege of Nursing, University of Shiga
    • , Noritaka HigashiAffiliated withClinical Research Center, Sagamihara National Hospital
    • , Masami TaniguchiAffiliated withClinical Research Center, Sagamihara National Hospital
    • , Tadao EnomotoAffiliated withDepartment of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center
    • , Xiao-Quan MaoAffiliated withDepartment of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health
    • , Hitoshi NakashimaAffiliated withDepartment of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University
    • , Chaker N. AdraAffiliated withDepartment of Medicine, Beth Israel Deaconess Medical Center
    • , Yusuke NakamuraAffiliated withLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo
    • , Mayumi TamariAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN) Email author 
    • , Taro ShirakawaAffiliated withLaboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN)Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health

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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, 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-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.