TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids

Kelan G. Tantisira, Eun Sook Hwang, Benjamin A. Raby, Eric S. Silverman, Stephen L. Lake, Brent G. Richter, Stanford L. Peng, Jeffrey M. Drazen, Laurie H. Glimcher, Scott T. Weiss

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naïve 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 PC 20 (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.

Original languageEnglish
Pages (from-to)18099-18104
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number52
DOIs
StatePublished - 28 Dec 2004

Keywords

  • Interaction
  • PC
  • Pharmacogenetics
  • T-bet

Fingerprint

Dive into the research topics of 'TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids'. Together they form a unique fingerprint.

Cite this