Published ahead of print on September 22, 2005, doi:10.1164/rccm.200503-505OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 1, January 2006, 64-70
A more recent version of this article appeared on January 1, 2006
Submitted on March 31, 2005
Accepted on September 22, 2005
T-Bet Polymorphisms are Associated with Asthma and Airway Hyperresponsiveness
Benjamin A Raby1*, Eun-Sook Hwang2, Kristel Van Steen2, Kelan Tantisira3, Stanford Peng4, Augusto Litonjua1, Ross Lazarus5, Cosmas Giallourakis6, John D Rioux6, David Sparrow7, Edwin K Silverman3, Laurie H Glimcher8, and Scott T Weiss3
1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA,
2 Harvard School of Public Health, Boston, MA, USA,
3 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA,
4 Departments of Internal Medicine, Pathology, and Immunology, Washington University School of Medicine, St. Louis, MO, USA,
5 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA,
6 The Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA,
7 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Veterans Administration Medical Center, Boston, MA, USA,
8 Harvard Medical School, Boston, MA, USA; Harvard School of Public Health, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: benjamin.raby{at}channing.harvard.edu.
Rationale: T-bet (TBX21 or T-box 21) is a critical regulator of T helper 1 lineage commitment and interferon gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR. Objectives: To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association. Methods: Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 asthmatics). 16 variants were genotyped in 580 nuclear families ascertained through asthmatic offspring from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function (FEV1), total serum immunoglobulin E (IgE) and blood eosinophil levels. Main Results: We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in Caucasian families using both additive (p=.02) or dominant models (p=.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC20, p=.02-.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR. Conclusions: These data suggest that T-bet variation contributes to airway responsiveness in asthma.
Key words: TBX21, T-box, single nucleotide polymorphism, Immunoglobulin E
This article has been cited by other articles:
|
|
|
|
 
D. M. Durrant, S. L. Gaffen, E. P. Riesenfeld, C. G. Irvin, and D. W. Metzger
Development of Allergen-Induced Airway Inflammation in the Absence of T-bet Regulation Is Dependent on IL-17
J. Immunol.,
October 15, 2009;
183(8):
5293 - 5300.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Y. Kim, M. Pichavant, P. Matangkasombut, Y. I. Koh, P. B. Savage, R. H. DeKruyff, and D. T. Umetsu
The Development of Airway Hyperreactivity in T-bet-Deficient Mice Requires CD1d-Restricted NKT Cells
J. Immunol.,
March 1, 2009;
182(5):
3252 - 3261.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Svensson, A.-M. H. Bergin, G.-B. Lowhagen, P. Tunback, L. Bellner, L. Padyukov, and K. Eriksson
A 3'-untranslated region polymorphism in the TBX21 gene encoding T-bet is a risk factor for genital herpes simplex virus type 2 infection in humans
J. Gen. Virol.,
September 1, 2008;
89(9):
2262 - 2268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Zhu and W. E. Paul
CD4 T cells: fates, functions, and faults
Blood,
September 1, 2008;
112(5):
1557 - 1569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. F. Werneck, G. Lugo-Villarino, E. S. Hwang, H. Cantor, and L. H. Glimcher
T-Bet Plays a Key Role in NK-Mediated Control of Melanoma Metastatic Disease
J. Immunol.,
June 15, 2008;
180(12):
8004 - 8010.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. G. Martin and T. Jo
Genetic Differences in Airway Smooth Muscle Function
Proceedings of the ATS,
January 1, 2008;
5(1):
73 - 79.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. C. Moore and S. P. Peters
Update in Asthma 2006
Am. J. Respir. Crit. Care Med.,
April 1, 2007;
175(7):
649 - 654.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. K. Silverman
Haplotype Thinking in Lung Disease
Proceedings of the ATS,
January 1, 2007;
4(1):
4 - 8.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Rangachari, N. Mauermann, R. R. Marty, S. Dirnhofer, M. O. Kurrer, V. Komnenovic, J. M. Penninger, and U. Eriksson
T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17
J. Exp. Med.,
August 7, 2006;
203(8):
2009 - 2019.
[Abstract]
[Full Text]
[PDF]
|
|
|
Copyright © 2005 American Thoracic Society
|
|
|
