Published ahead of print on September 22, 2005, doi:10.1164/rccm.200503-505OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200503-505OC
T-Bet Polymorphisms Are Associated with Asthma and Airway HyperresponsivenessChanning Laboratory, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center; Harvard Medical School; Harvard School of Public Health; Veterans Administration Medical Center; Harvard Partners Center of Genetics and Genomics; Boston; The Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts; Departments of Internal Medicine, Pathology, and Immunology, Washington University School of Medicine, St. Louis, Missouri; and Division of Molecular Life Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea Correspondence and requests for reprints should be addressed to Benjamin Raby, M.D.C.M., M.P.H., Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115. 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 IFN- 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 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma 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, total serum immunoglobulin E, and blood eosinophil levels. Main Results: We identified 24 variants. Evidence of association was observed between c.–7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.–7947 and three other variants were also associated with AHR (log-methacholine PC20, p = 0.02–0.04). 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: immunoglobulin E • single nucleotide polymorphism • T-box • TBX21 This article has been cited by other articles:
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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. 
