title: 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.
authors.affiliation: Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, Institute of Physical and Chemical Research (RIKEN), Tsurumi-ku, Kanagawa, Japan.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Akahoshi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Obara
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hirota
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Naomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Lei
authors.initials: L
authors.lastname: Cheng
authors.forename: Satoru
authors.initials: S
authors.lastname: Doi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyatake
authors.forename: Kimie
authors.initials: K
authors.lastname: Fujita
authors.forename: Noritaka
authors.initials: N
authors.lastname: Higashi
authors.forename: Masami
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Tadao
authors.initials: T
authors.lastname: Enomoto
authors.forename: Xiao-Quan
authors.initials: XQ
authors.lastname: Mao
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Chaker N
authors.initials: CN
authors.lastname: Adra
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamari
authors.forename: Taro
authors.initials: T
authors.lastname: Shirakawa
mesh_terms: D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D001241:Aspirin / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced* / Q000235:genetics*; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D004342:Drug Hypersensitivity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007564:Japan; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma; D001241:Aspirin