title: Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas.
abstract: High red meat intake has been linked with an increased risk of colorectal cancer and adenomas. During high temperature cooking of red meats, heterocyclic amines (HCAs) are generated; however, to be carcinogenic, they must be metabolized by enzymes including cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 (NAT1) and/or N-acetyltransferase 2 (NAT2). We have conducted a clinic-based case-control study of colorectal adenomas that focused on assessment of exposure to HCAs (estimated by use of a HCA database and meat cooking module) and modification of these exposures by genetic factors. We have previously reported that intake of MeIQx was associated with an increased risk of colorectal adenomas [overall association at 80th percentile, > 27.00 ng/day: odds ratio (OR) = 2.68, 95% confidence interval (CI) 1.58-4.55]. Here, we report our evaluation of whether variation in CYP1A2, NAT1 and/or NAT2 modify the association between HCAs and colorectal adenoma formation in 146 cases and 228 frequency-matched controls. The NAT1*10 allele was associated with a nonsignificant increased risk of colorectal adenomas (OR = 1.43; 95% CI 0.86-2.36). Further, when we analysed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake as a categorical variable, we observed a six-fold increase in adenoma risk among rapid NAT1 acetylators who consumed more than 27 ng a day (OR = 6.50; 95% CI 2.16-19.7), whereas among slow NAT1 acetylators, the increase in risk was two-fold (OR = 2.32; 95% CI 1.12-4.81). While suggestive, the results were not significantly different from each other on either an additive or multiplicative scale. In contrast, NAT2 genotype and CYP1A2 and NAT2 hepatic activity measured by caffeine urinary metabolites were not associated with adenoma risk, although an increase in risk with rapid CYP1A2 activity could not be ruled out (OR = 1.46; 95% CI 0.76-2.81). Moreover, there was no evidence that the effect of MeIQx was enhanced among subjects in any subgroup defined by variation in these measures. These results are compatible with the hypothesis that high HCA exposure is associated with an increased risk of colorectal adenomas, particularly in genetically susceptible subgroups. Further study of larger populations is needed to confirm and extend these observations.
authors.affiliation: Genetic Epidemioly Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA. ishiben@exchange.nih.gov
authors.forename: Naoko
authors.initials: N
authors.lastname: Ishibe
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sinha
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
authors.forename: Martin
authors.initials: M
authors.lastname: Kulldorff
authors.forename: Paul
authors.initials: P
authors.lastname: Strickland
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fretland
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Lang
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D003296:Cooking; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D004032:Diet; D005838:Genotype; D006571:Heterocyclic Compounds / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008460:Meat; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011804:Quinolines / Q000378:metabolism*; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D006571:Heterocyclic Compounds; D007527:Isoenzymes; D011804:Quinolines; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline