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Nutrient-Gene Interactions

Meat Consumption Patterns and Preparation, Genetic Variants of Metabolic Enzymes, and Their Association with Rectal Cancer in Men and Women^1,2

Maureen A. Murtaugh³, Khe-ni Ma, Carol Sweeney^*, Bette J. Caan and Martha L. Slattery

Health Research Center, Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT 84101; ^* Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN 54545; and Division of Research, Kaiser Permanente, Oakland, CA 94612

³To whom correspondence should be addressed. E-mail: mmurtaugh{at}hrc.utah.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Meat consumption, particularly of red and processed meat, is one of the most thoroughly studied dietary factors in relation to colon cancer. However, it is not clear whether meat, red meat, heterocyclic amines (HCA), or polycyclic aromatic hydrocarbons (PAH) are associated with the risk for rectal cancer. Rectal cancer cases (n = 952) and controls (n = 1205) from Utah and Northern California were recruited from a population-based case-control study between September 1997 and February 2002. Detailed in-person interviews regarding lifestyle, medical history, and diet were conducted. DNA was extracted from peripheral lymphocytes obtained from whole-blood samples, and glutathione S-transferase (GST)M1 enzyme and N-acetyl transferase (NAT)2 enzyme genotypes were assessed. Although energy and cholesterol intakes were higher among cases than controls, adjustment for confounders accounted for the differences. Increased consumption of well-done red meat [odds ratio (OR) 1.33 95% CI 0.98, 1.79] was associated with an (P = 0.04) increase in risk for rectal cancer among men. The mutagen index, calculated on the bases of reported amount, doneness, and method of cooking meat, was also positively but not significantly (P = 0.24) associated with risk of rectal cancer for men (OR 1.37 95% CI 0.98, 1.92). NAT2-imputed phenotype and GSTM1 did not consistently modify rectal cancer risk associated with meat intake. These data suggest that mutagens such as HCA that form when meat is cooked may be culpable substances in rectal cancer risk, not red meat itself.

KEY WORDS: • rectal cancer • meat • heterocyclic amines • polycyclic aromatic hydrocarbons

Meat consumption, particularly red and processed meat consumption, is one of the most thoroughly studied dietary risk factors for colon cancer. Meat was examined initially because of its fat content, which could influence the bile acid content of the gut, but has been studied more recently with regard to other attributes. Mutagen content (1,2), meat preparation (2), the role of meat in dietary patterns (3), and types of meat (4–6) have been studied. On the bases of other risk factors and site-specific analyses reported, it is highly plausible that the risk factors for colon and rectal cancer may be different. Some studies report stronger associations for distal tumors than proximal (7), although few studies have reported the association of meat consumption with risk for rectal cancer alone (2).

It is not clear whether the association between meat consumption and colorectal cancer is from the consumption of meat, or if it arises from meat preparation methods that generate higher levels of carcinogenic heterocyclic amines (HCAs),⁴ polycyclic aromatic hydrocarbons (PAHs), or other compounds. HCAs are formed as a by-product of reactions during the cooking of meat (beef, pork, lamb), poultry (chicken) and fish especially when they are char-broiled or roasted (8–14). Dietary exposure to HCAs has been a suspected risk factor for colorectal cancer since the 1970s (15). Exposure to PAH in food is one of the primary sources of exposure to PAH in the United States (16).

An inherited variation in metabolism of HCA and PAH compounds may modify cancer risk associated with these exposures. Metabolism of certain mutagenic forms of PAH can be detoxified by the glutathione S-transferase (GST)M1 enzyme. The GSTM1 null variant associated with no activity may, therefore, be associated with altered risk of cancers (17). The N-acetyl transferase (NAT)2 enzyme catalyzes O-acetylation of HCAs to form compounds that bind covalently to DNA (18); therefore, inherited low-activity variants may play a role in the etiology of rectal cancer.

We previously reported a slight increase in risk of colon cancer among men with the highest consumption of processed meat [odds ratio (OR) 1.4 95% CI 1.0–1.9] and the highest level of mutagen index (an estimate of exposure to mutagenic or carcinogenic substances, OR 1.3 95% CI 1.0–1.7) (1). Although no independent associations with colon cancer were observed for NAT2 and GSTM1 genotypes, associations with processed meat consumption (OR 1.5 95% CI 1.1–2.0) and the mutagen index (OR 1.3, 95% CI 1.0–1.7) were increased among those with the intermediate or rapid type acetylator phenotype. Interestingly, the associations of the mutagen index were stronger among both men and women with distal colon tumors compared with those with proximal tumors. The possibility that PAH may be directly related to rectal cancer risk or interact with PAH exposure is supported by the finding that GSTM1 absent genotypes are found more frequently among adenocarcinomas than in noncancerous polyps (7) and more distally in the intestinal tract (37% in the right colon, 44% in left colon, and 60% in the rectum).

We hypothesized that NAT2-imputed phenotype and GSTM1 genotype may interact with meat consumption or meat preparation to alter rectal cancer risk. Using methodology and variable definitions similar to those of our previous study (1), we investigated whether the associations between meat consumption, meat preparation method and the risk for rectal cancer in men and women from Utah and California were modified by NAT2 imputed phenotype and GSTM1 genotype.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Participants. The institutional review boards at each participating institution approved the methods. Cases with a first primary tumor in the rectosigmoid junction or rectum were identified between May 1997 and May 2001 using a rapid-reporting system. Case eligibility was determined in Northern California by the Surveillance Epidemiology and End Results Cancer Registries and in Utah using a rapid-reporting system. An on-line pathology reporting system was searched for rapid case ascertainment of rectal cancer cases at Kaiser Permanente Northern California Cancer Registry (KPMCP). Cases identified were confirmed through linkage to the KPMCP. Cases with a previous colorectal tumor were not eligible for the study. Cases with known (as indicated on the pathology report) familial adenomatous polyposis, ulcerative colitis, or Crohn’s disease were not eligible. In addition to these criteria, participants were between 30 and 79 y old at time of diagnosis, English speaking, and mentally competent to complete the interview.

Controls were frequency matched to cases by sex and by 5-y age groups. Education level and ethnicity did not differ between cases and controls of each gender (19). At the KPMCP, controls were randomly selected from membership lists, and in Utah, controls 65 y old were randomly selected from social security lists and controls <65 y old were randomly selected from driver’s license lists. The race/ethnicity of the study population was reported at the time of interview as 82% white, non-Hispanic, 7.3% Hispanic white, 4.1% African American, not Hispanic, 0.2% Hispanic African American, 4.6% Asian, 0.7% American Indian, and 1.1% multiple races/ethnicity. A total of 952 rectal cancer cases and 1205 matched controls are included in the analyses presented. Response rates were 65.2% for cases and 65.3% for controls; cooperation rates, or the number of people who participated from those whom we were able to contact, were 73.2% for cases and 68.8% for controls.

    Interview. Diet and other exposure data were collected during in-person interviews conducted by trained and certified interviewers using laptop computers. The interview took 2 h. Quality control methods used in the study were the same as those used in the colon cancer study and were described in detail elsewhere (7,8).

    Diet. Dietary intake was ascertained using an adaptation of the CARDIA diet history (8,12). Participants were asked to recall foods eaten for the calendar year occurring 2 y before their cancer diagnosis (cases) or recruitment into the study (controls), the frequency that they were eaten, serving size, and whether fats were added in the preparation. Nutrient information was obtained by converting food intake data into nutrient data using the Minnesota Nutrition Coordinating Center nutrient database Version 4.04_30. Additional information was gathered on usual doneness of meats (rare, medium-rare, medium-well done, and well done). Participants were asked how frequently red meats, fish, and poultry were fried, broiled, baked, or barbequed (cooked at high temperatures) and how frequently drippings were used in other foods or gravies. Variables included servings of particular foods or food groups (i.e., red meat, poultry, and red meat drippings) consumed per day, week, or year. The mutagen index was calculated as the frequency of red meat, poultry, and fish consumption prepared by frying, broiling, baking, or barbecuing plus the use of drippings from red meat, poultry, or fish, multiplied by the usual doneness of red meat, poultry, and fish (1 = rare, 2 = medium rare, 3 = medium-well, and 4 = well done) and the microwave factor (1 = microwave never used or used for thawing, 0.75 = sometimes used, 0.50 = often used, 0.25 = always used). A higher index reflects a higher intake of potentially mutagenic compounds.

    Genetic data. Blood was drawn from study participants and DNA was extracted. The GSTM1 null and present genotypes were detected using the multiplex PCR method described by Zhong and colleagues (20). The PCR products were run on a 2% agarose gel and stained with ethidium bromide. If the only product displayed is the 157 bp gene fragment, it is classified as GSTM1 null, whereas if both bands are present, it is classified as GSTM1 present.

Three variants of NAT2 were assessed, using the method of Bell et al. (21) to determine acetylator status of three variants that account for 90–95% of the slow acetylation phenotype in Caucasians. All three variants could be identified from one PCR product and be digested with three different restriction enzymes. The C481T variant was determined using a Kpn1 digest, the G590A variant using a Taq1 digest, and the G857A variant using a Bam H1 digest. Subjects with at least 2 variant alleles were classified as slow acetylators, whereas those with 1 or 0 variant alleles were classified as fast acetylators.

    Other information. Height (m) and weight (kg) were measured at the time of interview, and weight was reported for the 2 and 5 y before the interview. The BMI (kg/m²) was calculated for men and women. Physical activity data were collected using a detailed questionnaire (19,22). Estrogen-negative status was defined as postmenopausal women not taking hormone replacement and estrogen-positive status was defined as premenopausal women and postmenopausal women taking hormone replacement.

    Statistical methods. The SAS statistical package, version 8.2, CA, was used to conduct the analysis. We previously observed gender differences in diet-gene interactions associated with the risk of rectal cancer; therefore, gender-stratified analyses were pursued. Dietary data were assessed by determining risk across true medians, thirds, or quartiles of intake, or by other specific cut-off values defined for previous analyses (1) depending on the distribution of the data. The true medians, thirds, or quartiles were determined by the sex-specific intake distribution in the control population. In these models, the following variables were included: age at selection, BMI, physical activity, energy intake, dietary fiber, dietary calcium, and cigarette smoking status. Further confounding by cancer screening was assessed, but was found not to significantly confound associations. Linear trend was determined by evaluating the significance of linear association across the categorized variable. GSTM1 was analyzed as being present or absent; NAT2-imputed phenotype was analyzed as either slow or intermediate/rapid imputed. Interaction or effect modifications between meat-related variables and GSTM1 and NAT2-imputed phenotype were evaluated as the excess risk on both additive (23) and multiplicative scales. Interactions between meat and meat preparation variables and combinations of the genotypes or imputed phenotype were also evaluated on both additive and multiplicative scales.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Dietary intakes of cases and controls are described in Table 1. We reported previously that slightly fewer cases had a college education compared with controls (P = 0.01) (19), but race distribution did not differ between cases and controls (data not shown). Cases reported greater energy intake than controls, but the differences were not significant (P = 0.26 for men, P = 0.07 for women). Male cases consumed significantly more animal protein (g/d) than male controls. However, the proportion of energy intake from fat and protein did not differ between cases and controls of both genders. Cholesterol intake (mg/d) was greater among cases than controls of both genders. Female cases consumed more red meat (servings/wk) and processed meat (servings/wk) than female controls.

We examined the association of intake of red and processed meats and poultry with risk of rectal cancer and found no significant trends in men or women after adjustment for possible confounders of the association with rectal cancer (Tables 2, and 3). Further adjustment for sigmoidoscopy during the past 10 y did not change the interpretation of the results (data not shown). Although there was a tendency toward increased risk above the lowest level of intake of processed meats in women and among men in the highest tertile of intake, the associations were not significant (P for trend = 0.31 and 0.28, respectively).

We also examined the interaction of meat consumption, preparation, and mutagen index with NAT2-imputed phenotype and GSTM1 genotypes by gender. The associations of meat consumption and preparation with risk of rectal cancer generally did not differ between those with the slow NAT2 imputed phenotype and those with the rapid or intermediate acetylator phenotype (Tables 4, and 5). Among men (Table 4), consumption of well-done red meat was associated with a greater increase in risk among those who were rapid acetylators (P for multiplicative interaction = 0.09) compared with those who were slow acetylators. However, risk was increased with a high overall mutagen index among these slow acetylators. Among women (Table 5), having the rapid or intermediate phenotype and/or consumption of >4.2 servings of red meat per week, particularly among estrogen-negative women (n = 15 cases, 28 controls, OR 0.27 95% CI 0.10–0.74), or a high red meat mutagen index, particularly among estrogen-negative women (n = 12 cases, 13 controls OR 0.47 95% CI 0.14–1.57) was associated with an unexpected [relative excess risk due to interaction (RERI), P = 0.01, P for multiplicative interaction = 0.14] reduced risk of rectal cancer. Rectal cancer risk decreased among women who were slow acetylators and who ate high levels of red meat drippings; this was particularly true for estrogen-positive women (n = 23 cases, 29 controls, OR 0.34 95% CI 0.17, 0.68). Further adjustment for screening by sigmoidoscopy did not substantially change results (data not shown).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Our results are in contrast with earlier work on the association of meat with rectal cancer (2,25) and colorectal cancer (26–28). A Dutch prospective study suggested an increased risk of colorectal cancer with increased red meat intake among men, but a decreased risk associated with poultry and fish intake among women, which might be accounted for by the substitution of poultry and fish for red meat (28). Among Chinese in Singapore, protein and the ratio of meat:vegetable consumption were inversely associated with the risk for rectal cancer (3). Senesse et al. (29) observed opposite associations of fatty meats (positive) and lean meats (inverse) with the risk of adenomas in the right and left colon and rectum, suggesting that associations with rectal cancer could be substantially influenced by the composition of total meat intake or in the context of the whole diet. It is difficult to assess whether these different findings are related to differences in study methods, study populations, usual diets, and/or proportions of meats or preparation methods of meat in the diet.

Our results suggest a modest, nonsignificant increase in the risk of rectal cancer with consumption of well-done meat and white meat cooked at high temperatures (fried, baked, broiled, or barbecued) among men. A Swedish case-control study reported (2) a positive association of well-browned meats with rectal cancer, but did not report whether the results differed if they were stratified by gender. Our failure to find an association with meat intake per se suggests that HCAs or other carcinogens created by cooking meat at high temperatures could be responsible for the increase in risk. The biological plausibility is supported by the finding that the HCA 2-amino-3–8 dimethylimidazo quinoxaline (4,5) was associated with an increase in the risk for colorectal adenomas even after adjusting for consumption of red meat, suggesting that the HCA was the culpable substance, not red meat.

It is not immediately clear why gender differences were observed, but differences in background diet, levels of exposure, and metabolism cannot be ruled out. We examined gender differences because of our previous findings of differences in associations of intake of antioxidants to rectal cancer by gender (30). Although some findings were evident only in estrogen-positive or estrogen-negative women, small cell sizes limit our confidence in such findings. Any explanation at this point would be speculative and would have to be verified in other populations. It is also possible that these are chance findings with no biological relevance.

We found that acetylator status appeared to modify the risk of rectal cancer, but not consistently in the direction expected. In agreement with our previous report on colon cancer (1), men who had the rapid or intermediate acetylator phenotype and who consumed well-done meat had a greater increase in the risk for rectal cancer than men with the slow acetylator imputed phenotype. In women with the NAT2 slow acetylator imputed phenotype, use of red meat drippings at least once a week was associated with a decreased risk for rectal cancer. It is expected that for substances for which N-acetylation is a detoxification step, NAT2 slow acetylators are at increased risk, but for substances for which O-acetylation is an activation step, rapid acetylators would be expected to be at greater risk (31). It is not clear whether our findings actually represent differential risks from N-acetylation and O-acetylation because they could arise from multiple comparisons, residual confounding, interaction with another phase I or II metabolizing enzyme, or reflection of the metabolism of some other substance.

Although the possibility that PAH may be directly related to rectal cancer risk is supported by the finding that GSTM1 absent genotypes are found more frequently among cancerous tissues than in noncancerous tissues (7) and more distally in the intestinal tract, we found little evidence to support a direct association of GSTM1 genotype to risk for rectal cancer. An inverse association of fish or poultry to risk for colorectal cancer among those with GSTM1 present genotypes was reported (28) and attributed to residual confounding of other healthy habits. Although we did not find an inverse association with fish or poultry and rectal cancer risk, residual confounding of other healthy habits is plausible because PAH may be found in cereals and grain products, fruits, vegetables, and processed meat.

Heterocyclic amines and polycyclic aromatic hydrocarbons were not directly measured in this study. Instead, we inferred their intake from responses to questions about preference for doneness of meat and preparation method. Recall may be different for cases than controls based on the momentous event of cancer diagnosis, thus creating a potential bias in reported information. Strengths of the study include in-depth dietary assessment and questioning regarding meat preparation as well as rigorous quality control procedures (7,8). Gender differences are difficult to reconcile; however, few studies have shown gender-specific interactions of gene-environment associations, likely due to sample size issues. These findings, based on the largest case-control study of diet, lifestyle, and rectal cancer, enable us to assess potential gender-specific interactions with metabolic enzyme polymorphisms and add to the knowledge base for the etiology of rectal cancer.

	ACKNOWLEDGMENTS

 
We would like to acknowledge the contributions of Karen Curtin, Sandra Edwards, Roger Edwards, Michael Hoffman, Thao Tran, Leslie Palmer, Donna Schaffer, and Judy Morse to data collection and analysis components of the study.

	FOOTNOTES

 
¹ Funded by grant CA48998 to M.L.S. from the National Cancer Institute. This research also was supported by the Utah Cancer Registry, which is funded by Contract #N01-PC-67000 from the National Cancer Institute, with additional support from the State of Utah Department of Health, the Northern California Cancer Registry, and the Sacramento Tumor Registry.

² The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute.

⁴ Abbreviations used: GSTM1, glutathione S-transferase (GST)M1 enzyme; HCA, heterocyclic amines; KPMCP, Kaiser Permanente Northern California Cancer Registry; NAT2, N-acetyl transferase (NAT)2 enzyme; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; RERI, relative excess risk due to interaction.

Manuscript received 21 November 2003. Initial review completed 16 December 2003. Revision accepted 11 January 2004.

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TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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