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Published ahead of print on November 3, 2003, doi:10.1164/rccm.200307-973OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 2, January 2004, 214-219

A more recent version of this article appeared on January 15, 2004
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Submitted on July 20, 2003
Accepted on October 28, 2003

The Transforming Growth Factor {beta}1 Promoter Polymorphism C-508T is Associated with Asthma

Eric S Silverman1*, Lyle J Palmer2, Venkat Subramaniam3, Arlene Hallock3, Sheeba Mathew3, Joseph Vallone3, Debora S Faffe3, Toshiki Shikanai4, Benjamin A Raby5, Scott T Weiss5, and Stephanie A Shore3

1 Environmental Health, Harvard School of Public Health, Boston, MA, USA; Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 2 Medicine, Channing Laboratory, Boston, MA, USA; Epidemiology and Biostatistics, Case Western Reserve, Cleveland, OH, USA; Medical Research, Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Australia, 3 Environmental Health, Harvard School of Public Health, Boston, MA, USA, 4 Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 5 Medicine, Channing Laboratory, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: esilverm{at}hsph.harvard.edu.

Transforming growth factor {beta}1 (TGFB1) is increased in the lungs of asthmatics and may modulate airway inflammation and remodeling. Some genetic studies have found that a C to T single nucleotide polymorphism (C-509T) in the TGFB1 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 asthmatics and 170 controls without asthma. All individuals were Caucasians. Genotyping at 49 unlinked polymorphisms indicated that a subset of cases and all controls were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, gender, and genotype on case-control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a co-dominant model (OR = 2.98, 95% CI = 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 TGFB1 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 TGFB1 gene transcription.
Key words: Genetics, Population Stratification, Single Nucleotide Polymorphism, airway remodeling, YY1 transcription factor




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