Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services Bethesda, MD, USA.
Carcinogenesis. 2012 Jul;33(7):1332-9. doi: 10.1093/carcin/bgs158. Epub 2012 May 2.
Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.
肉中致突变物，包括杂环胺（HCAs）、多环芳烃（PAHs）和 N-亚硝胺（NOCs），可能通过 I 相和 II 相外源生物代谢酶（XME）的激活或解毒作用而参与结直肠癌的发生。本研究采用非条件逻辑回归估计比值比（OR）和 95%置信区间（CI），探讨了 5 种肉致突变物的摄入量以及 18 个 XME 基因中的>300 个单核苷酸多态性（SNP）与晚期结直肠腺瘤（1205 例病例和 1387 例对照）和结直肠癌（370 例病例和 401 例对照）之间的关系，这些病例和对照均来自前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验。通过含有详细肉类烹饪模块的食物频率问卷评估肉致突变物的饮食摄入量。在腺瘤研究中，观察到 2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉（MeIQx）摄入量与 NAT1 多态性 rs6586714 之间存在交互作用（P(交互) = 0.001）。在携带 GG 基因型的个体中，高 MeIQx 摄入量与腺瘤风险增加 43%相关（95%CI 1.11-1.85，P(trend) = 0.07），而 A 变体携带者则相反（OR = 0.50，95%CI 0.30-0.84，P(trend) = 0.01）。此外，我们观察到其他 XME 基因（UGT1A、CYP2E1、EPHX1、AHR 和 GSTM3）中的一些 SNP 存在提示性（P<0.05）的修饰作用，但在经过多重检验校正后这些作用并不显著。本研究对 XME 基因、肉致突变物和结直肠肿瘤风险进行了大型和全面的研究，发现 NAT1 多态性修饰了 MeIQx 摄入量与结直肠腺瘤风险之间的关联。
