TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids.
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 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 PC(20) associated with inhaled corticosteroid usage. The average PC(20) 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.
Tantisira
Kelan G
KG
Channing Laboratory and Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. kelan.tantisira@channing.harvard.edu
Hwang
Eun Sook
ES
Raby
Benjamin A
BA
Silverman
Eric S
ES
Lake
Stephen L
SL
Richter
Brent G
BG
Peng
Stanford L
SL
Drazen
Jeffrey M
JM
Glimcher
Laurie H
LH
Weiss
Scott T
ST
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000378:metabolism / Q000627:therapeutic use*; D000483:Alleles; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005973:Glutamine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology; D013997:Time Factors; D000098815:T-bet Transcription Factor
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D018076:DNA, Complementary; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D005973:Glutamine; D006639:Histidine; D003907:Dexamethasone