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

Springer Science and Business Media LLC - Tập 117 - Trang 16-26 - 2005
Mitsuteru Akahoshi1,2, Kazuhiko Obara1,3, Tomomitsu Hirota1, Akira Matsuda1, Koichi Hasegawa4, Naomi Takahashi1, Makiko Shimizu1, Kazuko Nakashima1,4, Lei Cheng4, Satoru Doi5, Hiroshi Fujiwara5, Akihiko Miyatake6, Kimie Fujita7, Noritaka Higashi8, Masami Taniguchi8, Tadao Enomoto9, Xiao-Quan Mao4, Hitoshi Nakashima2, Chaker N. Adra10, Yusuke Nakamura11, Mayumi Tamari1, Taro Shirakawa1,4
1Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan
2Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3Hitachi Chemical, Tokyo, Japan
4Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan
5Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan
6Miyatake Asthma Clinic, Osaka, Japan
7College of Nursing, University of Shiga, Shiga, Japan
8Clinical Research Center, Sagamihara National Hospital, Kanagawa, Japan
9Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan
10Department of Medicine, Beth Israel Deaconess Medical Center, Boston, USA
11Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Tóm tắt

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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