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Published ahead of print on November 3, 2003, doi:10.1164/rccm.200307-973OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 214-219, (2004)
© 2004 American Thoracic Society

Transforming Growth Factor-ß1 Promoter Polymorphism C–509T Is Associated with Asthma

Eric S. Silverman, Lyle J. Palmer, Venkat Subramaniam, Arlene Hallock, Sheeba Mathew, Joseph Vallone, Debora S. Faffe, Toshiki Shikanai, Benjamin A. Raby, Scott T. Weiss and Stephanie A. Shore

Department of Environmental Health, Harvard School of Public Health; Division of Pulmonary and Critical Care Medicine and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Australia

Correspondence and requests for reprints should be addressed to Eric S. Silverman, M.D., Department of Environmental Health, Harvard School of Public Health, 667 Huntington Avenue, Boston, MA 02115. E-mail: esilverm{at}hsph.harvard.edu

Transforming growth factor-ß1 (TGF-ß1) is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Some genetic studies have found that a C-to-T single-nucleotide polymorphism (C–509T) in the TGF-ß1 gene promoter may be associated with altered gene expression and asthma phenotype. To build on these data, we performed a case–control association study at this locus involving 527 subjects with asthma and 170 control subjects without asthma. All individuals were white. Genotyping at 49 unlinked polymorphisms indicated that a subset of case subjects and all control subjects were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, sex, and genotype on case–control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a codominant model (odds ratio, 2.98; 95% confidence interval, 1.45 to 6.25; p = 0.003). Total serum IgE, eosinophil count, and FEV1% predicted levels were not associated with this polymorphism. Furthermore, we show that the C–509T polymorphism alters TGF-ß1 promoter–reporter activity and promoter interactions with the transcription factor Yin Yang 1. We conclude that the T allele of C–509T is associated with the diagnosis of asthma and may enhance TGF-ß1 gene transcription.

Key Words: airway remodeling • genetics • population stratification • single-nucleotide polymorphism • Yin Yang 1 transcription factor




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