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

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-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.

Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis

“…Ylikoski and colleague also reported that TBX21 polymorphisms were not related to a Finnish asthmatic population (Ylikoski et al, 2004). A study on a Japanese population demonstrated the associations of one TBX21 polymorphism with aspirin-induced asthma, but not with other forms of asthma (Akahoshi et al, 2005). Raby and colleague recently demonstrated that TBX21 polymorphisms were associated with asthma and airway hyperresponsiveness in a North American population (Raby et al, 2006).…”

Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection

“…Susceptibility to asthma and airway hyper-responsiveness in asthmatic children has been associated with upstream SNPs in the TBX21 gene (Raby et al, 2006), and an SNP in the promoter region has been associated with aspirin-induced asthma in Japanese asthmatics. The latter SNP, with involves a substitution of a tyrosine with a cystein, leads to increased transcriptional activity of TBX21 (Akahoshi et al, 2005). Polymorphisms in TBX21 may be of importance in the treatment of asthma, since an SNP in TBX21 has been shown to enhance the effects of inhaled corticosteroid treatment in asthmatic children (Tantisira et al, 2004).…”

TBX21-1993T/C (rs4794067) polymorphism is associated with increased risk of chronic periodontitis and increased T-bet expression in periodontal lesions, but does not significantly impact the IFN-g transcriptional level or the pattern of periodontophatic bacterial infection

“…13 Taking into consideration the essential role of T-bet in Th1 responses development, the TBX21 (17q21.32) -1993T/C polymorphism (rs4794067) of the promoter region of T-bet gene has been associated with an increased binding affinity to Sp1 transcription factor and increased transcriptional activity of the TBX21 gene, resulting in a predisposition to a Th-1 biased immune response characterized by increased IFN-g secretion. 17,18 Indeed, numerous studies have associated the TBX21-1993T/C SNP with increased risk or early onset of different diseases, such as type I autoimmune hepatitis, 19 systemic lupus erythematosus, 18 childhood asthma 20 and aspirin-induced asthma. 17 Despite the previous association of Th1-type responses with periodontitis development, no study has investigated the possible influence of this SNP in periodontitis, although it has a potential functional influence in Th1-polarization.…”

“…17,18 Indeed, numerous studies have associated the TBX21-1993T/C SNP with increased risk or early onset of different diseases, such as type I autoimmune hepatitis, 19 systemic lupus erythematosus, 18 childhood asthma 20 and aspirin-induced asthma. 17 Despite the previous association of Th1-type responses with periodontitis development, no study has investigated the possible influence of this SNP in periodontitis, although it has a potential functional influence in Th1-polarization.…”