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

Le Marchand L, Donlon T, Seifried A, et al. Red meat intake, CYP2E1 genetic polymorphisms, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2002;11:1019-24.

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
2. Gene-disease association
4. Gene-gene interaction

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

Gene(s)
Identification of the following:

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

1. Gene name: CYP2E1, P450C2E
2. Chromosome location: 10q24.3-qter
3. Gene product/function: This is an ethanol-inducible cytochrome that can activate procarcinogens into reactive intermediates capable of forming adducts and damaging DNA, thereby playing an essential role in chemical carcinogenesis [1, 2]. The activation of nitrosamine, one of its substrates, has been associated with numerous cancers.
4. Alleles: Identified with restriction by RsaI, this polymorphism is in the 5’ flanking region of the gene’s promoter and has alleles designated as c1 (RsaI+) and c2 (RsaI-) [3]. The variant allele (RsaI+) causes loss of transcriptional regulation resulting in decreased CYP2E1 activity and/or inducibility. Interactive effects with alcohol dehydrogenase-2 (ADH2) have also been demonstrated [4, 5].

   A more recently discovered polymorphism is a 96-bp insertion in the regulatory region of the gene. The insertion has been associated with enhanced CYP2E1 metabolic activity in the presence of ethanol intake and obesity [6]. Other polymorphisms not addressed in this paper include one in intron 6 that is identified with restriction by DraI [7] and another in intron 7 identified with restriction by TaqI [8]

   
   
5. OMIM #: 124040

.

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

Nutritional: red meat, processed meat, salted/dried fish, oriental pickled vegetables

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

1. Colon cancer
2. Rectal 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: Primary adenocarcinoma of the colon or rectum
2. Exclusion Criteria: Not specified
3. Gender: Men and women
4. Race/ethnicity: Japanese (at least 75% heritage), native Hawaiians (any % heritage), and Whites
5. Age: Not specified
6. Time period: January 1994-August 1998
7. Geographic location: Oahu, Hawaii
8. Number of participants: 548 (71% participation rate)

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 cirteria: Presumably healthy participants of Hawaii State Department of Health survey, supplemented by Health Care Financing Administration participants aged > 65 years.
2. Matching variables: Sex, age, ethnicity
3. Exclusion Criteria: Not specified
4. Gender: Men and women
5. Race/ethnicity: Not specified
6. Age: Not specified
7. Time period: Not specified
8. Geographic location: Statewide over Hawaii
9. Number of participants: 656 (85% participation rate)

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

1. Environmental factors: Red meat (beef, pork, veal, lamb), processed meat (ham, bacon, sausage, luncheon meats), salted/dried fish (including taegu), oriental pickled vegetables (including tsukemono, kim chee, other pickled vegetables).
2. Exposure assessment: Self-reported diet questionnaire, followed by use of USDA nutrient database to compute nutrient intakes of food items and daily intakes.
3. Exposure definition: In case-patients, items eaten at least 12 times a year during year before onset of symptoms. In controls, items eaten during the previous 12 months.
4. Number of participants with exposure data: N (% of total eligible): Not specified

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

1. Gene: CYP2E1, RsaI polymorphism
2. DNA source: Blood sample
3. Methodology: Method of Le Marchand [9]
4. Number of participants genotyped: N (% of total eligible): 1160 (96%)

1. Gene: CYP2E1, 96-bp insertion polymorphism
2. DNA source: Blood sample
3. Methodology: Method of McCarver [6]
4. Number of participants genotyped: N (% of total eligible): 1148 (95%)

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 variants (Table 1).
2. Gene-disease association (Table 1).
3. Gene-environment association (Tables 2, 2a, 4).

Persons carrying alleles conferring high CYP2E1 activity (96-bp insertion polymorphism) are at increased risk for colorectal cancer. Persons who have this variant and have high intakes of red or processed meat are at even greater risk. This joint effect is even stronger when considering persons with low fruit and vegetable intakes.

Subject selection:

1. Controls were derived from two different sources, but no data were given for ethnic distributions in case-patients and controls.

2. Despite a good participation rate for obtaining blood samples, participation was low for interviews. Although interviewed and noninterviewed cases were comparable, the authors did not provide similar information for controls.

3. One-to-one matching was done at the interview stage, rather than on the basis of blood sample collection.

  Analysis:

1. Precision may have been lost because unconditional analysis was used, rather than conditional methods that would have correctly accounted for matched data.

2.  Although all ethnicities had different allele distributions, population stratification was not examined.

3. Alcohol consumption, an inducer of CYP2E1, was not controlled for in the analyses.

4.  Le Marchand et al.’s findings strengthen the argument that an interaction exists between the gene variants and food groups noted.

5.  Case-only odds ratios > 1 for meat groups and the insert variant warrant further investigation (1.24 for red meat with colon cancer; 1.39 and 1.33 for red and processed meat with rectal cancer). Control-only odds ratios were about 1, but selection bias should still be considered.

6. Though all interaction effects in modeling were non-significant, probably due to lack of power, these are important implications for future studies.

Consistency:

1. The finding that associates the 96-bp insert polymorphism with colorectal cancer is novel and further strengthened by investigation of interactions from established nutritional studies [10, 11].
2. The lack of significant association with RsaI polymorphisms is not as clear. A similar study [12] has shown an association, whereas those related to gastric [13] and esophageal [14] cancers have demonstrated protection