Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 52, Pages 18099-18104Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0408532102
Keywords
PC20; pharmacogenetics; T-bet; interaction
Categories
Funding
- NHLBI NIH HHS [HR16052, HR16046, HR16051, N01HR16044, N01HR16052, N01-HR-16049, HR16045, N01 HR16044, N01HR16050, HR16049, HR16047, HR16050, U01 HL65899, HR16048, N01HR16048, N01HR16049, N01HR16051, N01HR16045, N01HR16047, N01HR16046, U01 HL065899] Funding Source: Medline
- NIAID NIH HHS [P01 AI031541, U19 AI031541, AI31541] Funding Source: Medline
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TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naive T lymphocyte development and has been implicated in asthma pathogenesis. Specifically, the T-bet knockout mouse spontaneously develops airway hyperresponsiveness and other changes consistent with asthma. Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion. Here we demonstrate that the nonsynonymous variation in TBX21 coding for replacement of histidine 33 with glutamine is associated with significant improvement in the PC20 (a measure of airway responsiveness) of asthmatic children in a large clinical trial spanning 4 years. We note that this increase occurs only in the children randomized to inhaled corticosteroids and that it dramatically enhances the overall improvement in PC20 associated with inhaled corticosteroid usage. The average PC20 at trial end for subjects on inhaled corticosteroids possessing a variant allele was in the normal range for nonasthmatics. In cellular models, we show that the TBX21 variant increases T helper 1 and decreases T helper 2 cytokine expression comparably with wild type. TBX21 may thus be an important determinant pharmacogenetic response to the therapy of asthma with inhaled corticosteroids.
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