Modification by N-acetyltransferase 1 genotype on the association between dietary heterocyclic amines and colon cancer in a multiethnic study

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Abstract

Objective

Colorectal cancer incidence is greater among African Americans, compared to whites in the U.S., and may be due in part to differences in diet, genetic variation at metabolic loci, and/or the joint effect of diet and genetic susceptibility. We examined whether our previously reported associations between meat-derived heterocyclic amine (HCA) intake and colon cancer were modified by N-acetyltransferase 1 (NAT1) or 2 (NAT2) genotypes and whether there were differences by race.

Methods

In a population-based, case-control study of colon cancer, exposure to HCAs was assessed using a food-frequency questionnaire with a meat-cooking and doneness module, among African Americans (217 cases and 315 controls) and whites (290 cases and 534 controls).

Results

There was no association with NAT1*10 versus NAT1-non*10 genotypes for colon cancer. Among whites, there was a positive association for NAT2-“rapid/intermediate” genotype [odds ratio (OR) = 1.4; 95% confidence interval (CI) = 1.0, 1.8], compared to the NAT2-“slow” that was not observed among African Americans. Colon cancer associations with HCA intake were modified by NAT1, but not NAT2, regardless of race. However, the “at-risk” NAT1 genotype differed by race. For example, among African Americans, the positive association with 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) was confined to those with NAT1*10 genotype (OR = 1.8; 95% CI = 1.0, 3.3; P for interaction = 0.02, comparing highest to lowest intake), but among whites, an association with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was confined to those with NAT1-non*10 genotype (OR = 1.9; 95% CI = 1.1, 3.1; P for interaction = 0.03).

Conclusions

Our data indicate modification by NAT1 for HCA and colon cancer associations, regardless of race. Although the at-risk NAT1 genotype differs by race, the magnitude of the individual HCA-related associations in both race groups are similar. Therefore, our data do not support the hypothesis that NAT1 by HCA interactions contribute to differences in colorectal cancer incidence between African Americans and whites.

Introduction

Colorectal cancer incidence rates have been declining in the U.S., with the steepest decline since 1990, especially among non-Hispanic whites [1]. Incidence rates (100,000/year) between 2000 and 2004 were higher among African-American males (72.6) and females (55.0), compared to whites males (60.4) and females (44.0) [2]. Contributing factors to the higher rates of colorectal cancer among African Americans may include dietary intake [3] and/or eating behavior [4], genetic variation at metabolic loci [5] and/or joint effects of both dietary factors and genetic susceptibility [6].

Heterocyclic amines (HCAs) are mutagens and animal carcinogens that are formed when meat is cooked at high temperatures by methods such as pan frying until it is well-done or has a charred appearance [7]. Consumption of pan-fried, well-done meat is a surrogate for HCA and PAH exposure [8], and may be positively associated with colon cancer [9]. Differences in meat intake patterns by doneness and cooking method have been observed among a population-based control sample of African Americans and whites in North Carolina, U.S. For example, among African-American controls, greater intake was observed for pan-fried red meat, well/very well-done red meat, white meat and pan-fried chicken intake, and the HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), compared to white controls. In contrast, greater grilled/barbecued red meat intake was observed among white controls, compared to African-American controls [10].

HCAs require activation in order to exhibit carcinogenic potential [11]. The initial N-hydroxylation step occurs in the liver, and is catalyzed by cytochrome p4501A2 (CYP1A2) [12]. The resulting N-hydroxy HCA derivatives are thought to be stable enough to circulate to the colon [13], [14] where they are activated by N-acetyltransferase 1 (NAT1) and 2 (NAT2) through O-acetylation leading to the formation of highly reactive N-acetoxy esters [15]. These compounds undergo spontaneous hydrolysis to form arylnitrenium ions; which have the potential to covalently bond with DNA to form adducts and thereby increase risk of mutagenesis and possibly colon cancer [16], [17]. NAT1 and NAT2 expression in hepatic, as well as extrahepatic human tissues has been well documented, with recent mRNA localization to the surface epithelial cells of the colon and of the crypts of Lieberkuhn [18].

Interindividual differences in the acetylation or metabolic activation of HCAs have been reported [19]. In addition, NAT1 and NAT2 genotype frequencies vary by race [19], [20], suggesting that racial differences in genetic susceptibility to HCAs may contribute to differences in colorectal cancer risk. Although several epidemiologic studies have evaluated whether genetic susceptibility at the NAT loci modify the association between surrogates of HCA exposure (e.g. meat doneness or cooking method) on risk of colon cancer [21], [22], [23], [24], few data are available that measure individual HCA compounds in a multiethnic population-based sample. We investigated whether our previously reported findings [10] were modified by NAT1 or NAT2 genotype, and whether there were differences by race.

Section snippets

Study population

Cases and controls of the North Carolina Colon Cancer Study were selected from 33 counties in North Carolina, U.S., and frequency matched to cases by race (African American, white), age (<65, ≥65 years), and sex [25]. Details of the study design have been previously described [10]. In brief, cases were selected through a rapid ascertainment system [26] established in conjunction with the North Carolina Central Cancer Registry. Cases were eligible if they were between 40 and 84 years of age at

Results

NAT1 and NAT2 allele and genotype frequencies are presented in Table 1. Genotype frequencies among controls were in HWE for NAT1 (P = 0.98 among African Americans, P = 0.65 among whites, with d.f. = 3), and for NAT2 (P = 0.55 among African Americans, P = 0.80 among whites, with d.f. = 4). Among controls, we observed higher frequencies of the NAT1*10, NAT2-rapid, and NAT2-intermediate genotypes among African Americans, than among whites. There was no association with colon cancer for NAT1*10 versus

Discussion

Racial disparities for colon cancer cannot be explained solely by socioeconomic, behavior, environmental, lifestyle factors, or genetic factors, rather explanations for these disparities may include interactions between all of these factors [41]. Using data from a population-based case-control study, we observed statistically significant interaction between meat-derived HCA intake and NAT1 genotype, regardless of race. In addition, our data suggest that NAT1 acetylation of HCAs differs by race,

Acknowledgements

This research was supported, in part, by grants from the National Institutes of Health T32 DK07634, R01 CA66635, P30-DK34987, NIEHS P30-ES10126, and P30-CA16086.

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