March 22, 2004 Access past issues

Reviewed by: Seymour Williams Rollins School of Public Health Emory University

The Health Outcome

Asthma is an inflammatory condition of the lung characterized by episodic and reversible airway obstruction. In 2001, asthma was reported as currently affecting 20.3 million people in the US , with 14 million being adults and the rest children. In addition to significant absences from work and school, asthma resulted also in 11.3 million office-based physicians’ visits, 1.3 million hospital outpatient department visits, and 1.7 million hospital emergency department visits in 2001. The number of deaths associated with asthma in 2001 was 4,269 with a rate of 1.5 deaths per 100,000.(1)

There is no definitive test for the diagnosis of asthma, which is clinically determined from a consistent history, physical examination and possibly spirometry and allergy testing.(2)

The cause of new onset asthma is believed to have a very strong genetic component along with environmental factors (e.g. environmental tobacco smoke) that trigger and exacerbate asthma symptoms.

Asthma is considered a complex polygenic disease indicating that multiple genes contribute towards developing susceptibility. In most cases, environmental exposure and requisite sensitivity are considered necessary to develop the asthma phenotype.

Multiple genes have been associated with asthma.(3) This study examined the role of TGFB1 (tumor growth factor beta 1), the gene products of which are increased in the lungs of people with asthma and airway inflammation. In previous studies, the polymorphism has been associated with increasing asthma severity.(4)

This paper describes the association between the TGFB1 C-509T promoter polymorphism and asthma and addresses some of the previously encountered confounders and additionally describes whether the gene is a functional variant responsible for the association with asthma.

The Finding

Silverman et al. have reported that the T allele and TT genotype of the TGFB1 C-509T polymorphism was positively associated with diagnosis of asthma in a case control study of unrelated white men and women in the United States.(5)  This polymorphism is associated with asthma severity and the protein is increased especially in persons with severe asthma.(2) The 527 cases had been previously recruited for an asthma medication trial and had moderate to severe asthma as defined by the American Thoracic Society (compatible history and reversibility of airflow by beta agonist or methacholine sensitivity testing). The 170 controls were selected from and characterized in the Environmental Medicine Genome Bank {EMGB}, which is composed of US army recruits from across the country in basic training. All the cases and controls were genotyped and other information was collected including IgG levels, eosinophil count and the percent predicted values for Forced Expiratory Volume in one second (% predicted FEV1). Genotyping at 49 unlinked markers was done on 311of the 527 cases and 170 of the controls to address population stratification. The T allele and the TT genotype under a codominant model were positively associated with the diagnosis of asthma (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. The authors also reported results of an in vitro study showing that the C-509Tpolymorphism altered TGF-beta1 promoter-reporter activity and promoter in tera ctions with the transcription factor Yin Yang 1. They concluded that the T allele of C-509T is associated with the diagnosis of asthma and may enhance TGF-beta1 gene transcription.

Public Health Implications

This study accounted for population stratification, but given different sources of cases/controls there is likely lack of comparability for environmental factors between the groups. The lack of association between the TGF-beta1 C-509T polymorphism and other very important measures of asthma severity (IgE levels, eosinophil and % predicted FeV1) is concerning. It is premature to attempt to assess the public health implications of these findings given the complexity of asthma and the need for additional studies. The association of TGFB1 promoter polymorphism C-509T and asthma is biologically plausible, and this study confirms the polymorphism’s functional effect. Additional research is needed, not just to replicate this study in other populations but to identify other gene-gene and multiples of gene-gene and gene-environment interactions.

References

1. http://www.cdc.gov/nchs/fastats/asthma.htm
2. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987 Jul; 136(1):225-44.
3. Hakonarson H, et al. Genetic Analyses in Asthma. Am J Pharmacogenomics 2002:2(3):155-166
4. Pulleyn LJ, Newton R, Adcock IM, Barnes PJ. TGFbeta1 allele association with asthma severity. Hum Genet. 2001 Dec; 109(6):623-7. Epub 2001 Oct 27.
5. Silverman, Eric S, et al. Transforming growth factor-beta1 promoter polymorphism C-508T is associated with asthma. AJRCCM 2003 November; 169:214-219s.