Reference
Complete the bibliographic reference for the article according to AJE format.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

2. Gene-disease association

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study

Hypothesis: The C-509T polymorphism in the TGF beta 1 gene promoter is associated with asthma in a large population of well characterized cases with asthma compared with genetically matched controls.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: TGFB1
2. Chromosome location: 19q13.1-q13.3
3. Gene product/function: multiple function peptide involved in the suppression of cell proliferation, inflammatory immune response and blood vessel growth and deposition of extracellular matrix
4. Alleles: C-509T, which is in the promoter region, so is non-coding.
5. OMIM #: 190180

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

None

Health outcome(s)
Identification of the major health outcome(s) studied

Case or control status for asthma

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

1. Disease case definition
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Disease case definition: Moderate to severe asthma as defined by the American Thoracic Society (compatible history and reversibility of airflow by beta agonist or methacholine sensitivity testing with spirometry à 40-85 % FEV1).
2. Exclusion criteria: smoker, less than 18 years or more than 45 years of age or having significant co-morbid condition
3. Gender: males and females
4. Race/ethnicity: white (Caucasian) only
5. Age: mean age 33.7 years for cases (standard deviation 13.7)
6. Time period: ‘not specified’
7. Geographic location: United States
8. Number of participants: 527

1. Control selection criteria
2. Matching variables
3. Exclusion criteria
4. Gender
5. Race/ethnicity
6. Age
7. Time period
8. Geographic location
9. Number of participants

1. Control selection criteria: Without asthma, selected from and characterized in the Environmental Medicine Genome Bank (EMGB), which includes US army recruits from across the country in basic training; assessed for sex, age, history of asthma, or exercise induced bronchospasm, spirometry and total serum IgE.
2. Matching variables: Genetic matching was done on 311of the 527cases and 170 of the controls at 49 unlinked markers(1).
3. Exclusion criteria: Asthma, using medications for asthma regardless of symptoms, reliable diagnosis of obstructive airway disease at any age Gender: males and females
4. Race/ethnicity: white (Caucasian) only
5. Age: 25.7 years for controls (Standard deviation 7.6)
6. Time period: ‘not specified’
7. Geographic location: United States
8. Number of participants: 170

Cohort definition
For study designs 2, 3, and 6, define the following if available:

1. Cohort selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (% of total eligible)

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: TGFB1 promoter C-509T
2. DNA source: peripheral blood
3. Methodology: Restriction fragment length polymorphism analysis, described in online supplement to article Silverman et al (2)(a)
4. Number of participants genotyped: 697 (100% of total eligible)

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

Genotype frequency and disease association

* UOR - Univariate Odds Ratio
+ Multivariate Odds Ratio (adjusted for age and sex)

The authors found a strong positive association between the T allele and the TT genotype of the TGF b 1 promoter gene (C-508) with the diagnosis of asthma among white adults ages 18 to 45 years.

Strengths:
Biologically plausible, large number of cases, population stratification addressed using 49 other unlinked markers, “strict” application of asthma case definition, and previously described association. Authors’ assessment of gene function suggests a functional role of the gene polymorphism, adding to the biologic plausibility.

Weaknesses:
The study base of the case and control subjects may not be the same, especially for environmental exposures. No association of genotype with FEV1%, IgE levels or eosinophil count.

Concerns:
The lack of association with the % FEV1, IgE levels and eosinophil count may be related to confounding due to the lack of a “gold standard” case definition for asthma. There are many genes related to the phenotype of asthma.(3); the TGFB1 gene also is involved in many other conditions (lung and non lung) and it may be have limited specificity or sensitivity as a marker for asthma.

References

1. Rebecca M. Baron, et al. DNA Sequence Variants in Epithelium-Specific ETS-2 and ETS-3 Are Not Associated with Asthma. Am J Respir Crit Care Med 2002; 166: 927-932,

2. Silverman, Eric S, et al. Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma. AJRCCM 2003 November; 169:214-219s. Online supplement

3. Hakonarson H, et al. Allelic frequencies and patterns of single-nucleotide polymorphisms in candidate genes for asthma and atopy in Iceland . Am J Respir Crit Care Med 2001 Dec 1;164(11):2036-44.