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

1. Gene-disease association
2. Gene-environment interaction

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

This study tests the hypothesis that individuals with low activity COMT genotypes will have less rapid O-methylation of tea catechins, and more apparent benefit from tea polyphenols; whereas, individuals with high activity COMT genotype will have more rapid elimination of tea catechins, and therefore the benefit of tea consumption will be less apparent.

Gene(s)
Identification of the following:

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

1. Gene name: Catechol-O-Methyltransferase (COMT) Gene
2. Chromosome location: 22q11.21
3. Gene product/function: enzyme COMT / catalyzes the o-methylation of endogenous catechol-amines and other catechols, including tea catechins and catechol estrogen.
4. Alleles: Low activity - COMT L allele; High activity - COMT H allele (3-4 fold difference in COMT activity between each allele)
5. OMIM #: 116790

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

Black tea or green tea intake

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

Breast Cancer

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: Women identified through the Los Angeles County Cancer Surveillance program as Chinese, Japanese, or Filipino, between the ages of 25 and 74 years at the time of diagnosis, with an incidence of breast cancer on or after January 1,1995 .
2. Exclusion criteria: Not specified
3. Gender: Female Race/ethnicity: Asian/ Chinese, Japanese, Filipino
4. Age: 25-74 years
5. Time period: January 1, 1995 - December 2001
6. Geographic location: Los Angeles County , California
7. Number of participants: 952 interviewed, blood obtained on 589 cases; Total - 589 cases in study analysis.

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: Women between the ages of 25-74, living in the same neighborhood as cases at the time of their diagnosis, and within a house specified by a standard algorithm.
2. Matching variables: frequency matched by specific Asian ethnicity and 5 year age group
3. Exclusion criteria: Not specified
4. Gender: Female
5. Race/ethnicity: Asian/ Chinese, Japenese, Filipino
6. Age: Not specified, but because frequency matched on age must be between 25-74 years
7. Time period: January 1, 1995 - December 2001
8. Geographic location: Los Angeles County , California
9. Number of participants: 822 interviewed; blood obtained from 564 controls; Total - 564 controls in study analysis.

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

1. Environmental factor: Tea intake
2. Exposure assessment:
   Food frequency questionnaire (measures frequency of intake and amount of beverage consumed each time)
3. Exposure definition: "Non-tea drinkers" versus "Tea-drinkers" = categorized into women who drank black tea only, women who drank green tea only, and women who drank a combination of black and green teas. "Tea-drinkers" further subcategorized into = 85.7ml/day, 85.7-209.4 ml/day, and > 209.4 ml/day.
4. Number of participants with exposure data: N = 99.8% Two Filipino controls unaccounted for in data, with no explanation from authors.

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

1. Gene: Catechol-O-Methyltransferase (COMT) gene
2. DNA source: Blood
3. Methodology: Genomic DNA was extracted from bloo

   lymphocytes and purified. Genotyping was performed by fluorogenic 5'-nuclease assay. Oligonucleotide primers: GC009for and GC009rev Fluorogenic oligonucleotide probes: GC009F labeled with 6-FAM to detect the L allele, and GC009C labeled with CY3 to detect the H allele. 12 controls were used to define parameters for identifying genotypes at each locus in experimental samples.

   
   
4. Number of participants genotyped: N = 99.8%   Two Filipino controls unaccounted for in data, with no explanation from authors.

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

Gene-Disease association: Association between COMT genotype and breast cancer in Asian-American Women

The presence of low activity COMT L allele is not significantly protective across all subjects.

(a) Conditional logistic regression models with matched sets defined jointly by 5 year age range, Asian ethnicity, and birthplace. In ethnicity specific analysis, the model includes age and birthplace.
(b) CI = Confidence Interval
(c) Prevented Fraction: (1-OR)*proportion of controls with protective factor

Gene-Disease Association stratified by ethnicity:

(a) Conditional logistic regression models with matched sets defined jointly by 5 year age range, Asian ethnicity, and birthplace. In ethnicity specific analysis, the model includes age and birthplace.
(b) CI = Confidence Interval
(c) Prevented Fraction: (1-OR)*proportion of controls with protective factor

The presence of low activity COMT L allele is significant for Filipino ethnicity. The protective effect attributable to the presence of the COMT L allele is 17.40%. This significance could be due to the small sample size of Filipinos with the COMT L allele.

Gene-Environment Interaction:
Risk of Breast Cancer in association with intake of tea and COMT genotype in Asian-American Women.

Measuring the joint impact of COMT genes and tea intake exposure, across all subjects the presence of low activity COMT L allele and drinking tea is significantly protective with a 16.5% prevented fraction. The presence of the low activity COMT L allele among Japanese tea drinkers is also significantly protective with a 12.4% prevented fraction.

(a) Conditional logistic regression models with matched sets defined jointly by 5 year age range, Asian ethnicity, and birthplace. CI = Confidence Interval
(b) Prevented Fraction: (1-OR)*proportion of cases with protective factor (Proportion of cases protected from breast cancer attributable to tea intake exposure) Negative PF's are not reported.
(c) Conditional logistic regression models with matched sets defined jointly by 5 year age range, Asian ethnicity, and birthplace; controlling for education, age at menarche, pregnancy, current BMI, menopausal status, use of menopausal hormones, intake of soy, intake of dark green vegetables, smoking history, alcohol intake, coffee intake, and physical activity.

Gene-Environment Interaction Stratified by Ethnicity:

(a)Conditional logistic regression models with matched sets defined jointly by 5 year age range, Asian ethnicity, and birthplace. CI = Confidence Interval
(b) Prevented Fraction: (1-OR)*proportion of cases with protective factor (Proportion of cases protected from breast cancer attributable to tea intake exposure) Negative PF's are not reported.
(c) Conditional logistic regression models with matched sets defined jointly by 5 year age range, Asian ethnicity, and birthplace; controlling for education, age at menarche, pregnancy, current BMI, menopausal status, use of menopausal hormones, intake of soy, intake of dark green vegetables, smoking history, alcohol intake, coffee intake, and physical activity.

The presence of the low-activity COMT L allele by itself did not have a significant protective effect on breast cancer among all the Asian-American women. Though it did appear to have a significant effect among Filipino ethnicity, this may have been due to the small numbers following stratification by ethnicity. The combination of the presence of low-activity COMT L allele with tea drinking, whether black tea only, green tea only, or the both green and black teas, revealed a significant protective effect across all Asian-American subjects. This study showed the opposing effects COMT genes may have on the risk of breast cancer. Alone, the presence of low-activity COMT L allele may have a disadvantageous association to the risk of breast cancer. However, the gene-environment interaction of low-activity COMT L allele with tea drinking can be beneficial in reducing breast cancer risk.

The hypothesis of the study depends on the assumption that methylated polyphenols are "less protective," which has no evidence to support it. Further studies would have to be conducted to test this assumption. Previous studies have shown significant increased risk of breast cancer among post-menopausal women and obesity, however these covariates were not controlled for when the association between COMT genotype and tea drinking was stratified by ethnicity type. This may have been due to small numbers to compare, which would require a larger sample size in future studies so that these confounding factors may be controlled for. Another concern is the small number of cases with COMT LL genotype in the study. The frequencies for the L allele were in Hardy-Weinberg equilibrium for all the controls and the Chinese and Japanese cases, but not for the Filipino cases. This demonstrates that the lower number of Filipino cases and COMT LL genotype may be a fallacy in this study, and the results may not be generalizable to the entire Los Angeles County Asian-American female population.

The authors do not report the number of cases that were eligible for the study but did not participate, which does not allow us to estimate selection bias thoroughly. We know that the study had only 62% of cases and 68% of controls give blood specimens, which is not a very high rate. Future studies may want to practice another method of attaining genomic DNA. Though a minor conflict, the authors were inconsistent in the number of controls they analyzed throughout the study. In reporting their method of attaining controls, they stated that they had a final sample of 563 controls for analysis. When reporting their statistical analysis, they stated that they had 564 controls in the analysis. However, in presenting their data in their tables, the controls add up to a total of only 562. Though the total study population is large, once stratified into COMT genotype and ethnicity the missing controls appear to come from the Filipino ethnicity which is already small in size in respect to the other ethnic groups.

Further studies may wish to explore if these findings may be generalized across other ethnic groups and therefore a broader population.