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

Yokoyama T, et al. Alcohol Flushing, Alcohol and Aldehyde Dehydrogenase Genotypes, and Risk for Esophageal Squamous Cell Carcinoma in Japanese Men. CEBP. 2003 Nov; 12: 1227-1233.

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. Prevalence of gene variant: ADH2 and ALDH2
2. Gene-disease association: esophageal cancer and surrogate for ALDH2
3. Gene-environment interaction: surrogate for ALDH2 and alcohol drinking
4. Gene-gene interaction: ADH2 and ALDH2
5. Genetic test evaluation: questionnaire

1. Evaluate the reliability of an alcohol flushing questionnaire for detecting inactive ALDH2 ( genotype ) – sensitivity and specificity.
   
2. Evaluate predictive model of esophageal cancer risk based on this questionnaire.

Gene(s)
Identification of the following:

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

1. Gene name: ALDH2, Aldehyde Dehydrogenase 2
2. Chromosome location: 12q24.2
3. Gene product/function: ethanol metabolism
4. Alleles: 2*1/2*1, 2*1/2*2, 2*2/2*2
5. OMIM#:100650

1. Gene name: ADH2, Alcohol Dehydrogenase 2
2. Chromosome location: 4q22
3. Gene product/function: ethanol metabolism
4. Alleles: 2*1/2*1, 2*1/2*2, 2*2/2*2
5. OMIM#:103720

1. drinking alcohol ( never/rare, light, moderate, heavy, ex-drinker )
2. frequency of drinking strong alcoholic beverages straight ( frequently, sometimes,never) ( No further description of this measure is given )
3. smoking ( pack-years: 0, < 30, ≥ 30)
4. Green-yellow vegetable intake ( 5 levels )
5. Fruits intake ( 5 levels )

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

1. esophageal cancer
   

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

1. Case-control Study

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

1. Disease case definition: male Japanese patients with primary esophageal squamous cell carcinomas undergoing treatment at four major Japanese Hospitals and registered between September 2000 and December 2001.

2a. Inclusion Criteria: age between 40-79yr old, newly diagnosed by histology, within 3 yrs of registration

2b. Exclusion criteria: Alcoholic patients diagnosed as having esophageal cancer at the National Institute on Alcoholism, Japan; Esophageal cancer patients registered in the authors’ previous study between 1998 and 1999

3. Gender: Male

4. Race/ethnicity: Japanese

5. Age: 40-79 years

6. Time period: enrollment during September 2000 and December 2001

7. Geographic location: Tokyo, Kawasaki, Osaka Japan

8. Number of participants: N ( % of total eligible ) 234/236 patients ( 99% ) --> 233 completed the questionnaire ( 233/236 ) ( 98.7% )

 

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 (% of total eligible)

1. Control selection criteria: cancer-free patients who visited two Tokyo clinics for annual health checkups between September 2000 and December 2001

2. Matching variables: none

3. Exclusion criteria: not specified

4. Gender:Male

5. Race/ethnicity: Japanese

6. Age: 40-79 years

7. Time periods: between September 2000 and December 2001

8. Geographic location: Tokyo, Japan

9. Number of participants: 634 ( 86% ) --> 610 completed the questionnaire ( 610/634= 96% ) but 83% of original eligible.

 

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

Environmental factors considered for interaction:

1. Exposure assessment: self-reported questionnaire

2. Exposure definition: alcohol drinking : self-classification of never, current, ex-drinker. Current drinkers were further classified into rare, light, moderate and heavy based on the frequency and type of alcohol beverage consumed.

3. Number of participants with exposure data: N ( % of total eligible ) 234/236 patients ( 99% ) for cases and 634 ( 86% ) for controls.

Environmental factors considered as potential confounders:

1.smoking ( pack years )

2.frequency of drinking strong alcoholic beverage straight ( this is a different frequency measure than the exposure variable of alcohol drinking as described in Table 1 )

3.green-yellow vegetable intake

4.fruits intake

 

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

1. Gene: ALDH2, ADH2
2. DNA source: lymphocyte
3. Methodology: PCR-RFLP
4. Number of participants genotyped: N ( % eligible ) 234/236 patients ( 99% ) for cases and 634 ( 86% ) for controls

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

• Table 1
• Table 2
• Table 3
• Table 4
• Table 5
• Table 6
• Table 7
• Table 8

• This simple questionnaire can reliably detect inactive ALDH2 and predict risk for esophageal cancer
• ADH2 modifies the association between flushing response and ALDH2 genotype
• This questionnaire may be a cost-effective approach in identifying high risk patients in clinical setting
• This questionnaire can be used in lieu of costly genetic analysis in a large epidemiologic study

• Selection bias: control selection and differential participation rate
• Misclassification bias: covariates (measurement bias ), flushing response (recall bias )
• Sensitivity and specificity differ between controls and cases modified by ADH2
• Restricted homogenous population: male, 40-70 y.o. Japaneses (reduces potential for population stratification )
• Choice of study population is appropriate and relevant for the gene, environmental exposure and the outcome studied
• Strong association but wide confidence interval due to small numbers
• High prevalence of genotype and exposure in the study population
• Identifying high risk individuals for early screening of esophageal cancer is an important public health issue in this population
• This case-control study is the first large study to confirm the association of these genotypes and esophageal cancer in non-alcoholic population.