TY - JOUR
T1 - Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma
AU - Akahoshi, Mitsuteru
AU - Obara, Kazuhiko
AU - Hirota, Tomomitsu
AU - Matsuda, Akira
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
N1 - Funding Information:
Acknowledgements This work was supported by grants-in-aid from the Ministry of Health, Labor, and Welfare, the Japan Science and Technology Corporation, and the Japanese Millennium project. We thank all participants in the study. We also thank Hiroshi Sekiguchi and Miki Kokubo for technical assistance and Chinatsu Fukushima for providing data on the patients.
PY - 2005/6
Y1 - 2005/6
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-005-1285-0
DO - 10.1007/s00439-005-1285-0
M3 - Article
C2 - 15806396
AN - SCOPUS:20344378203
VL - 117
SP - 16
EP - 26
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 1
ER -