Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI 96813, USA.
Carcinogenesis. 2011 Feb;32(2):203-9. doi: 10.1093/carcin/bgq237. Epub 2010 Nov 16.
Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and Native Hawaiians to investigate the association of genetic variation in the PAH and HAA bioactivation pathway (CYP1A1, CYP1A2, CYP1B1, AHR and ARNT) identified through sequencing with risk of colorectal neoplasia, as well as their interactions with smoking and intakes of red meat and HAAs. The A allele for ARNT rs12410394 was significantly inversely associated with CRC [odds ratios (ORs) and 95% confidence intervals (CIs) for GG, AG and AA genotypes: 1.00, 0.66 (0.48-0.89), 0.54 (0.37-0.78), P(trend) = 0.0008] after multiple comparison adjustment. CYP1A2 rs11072508 was marginally significantly associated with CRC, where each copy of the T allele was associated with reduced risk (OR: 0.72, 95% CI: 0.58-0.88, P(trend) = 0.0017). No heterogeneity of genetic effects across racial/ethnic groups was detected. In addition, no significant interaction was observed after adjusting for multiple testing between genetic variants and pack-years of smoking, intake of red meat or HAAs (PhIP, MeIQx, Di-MeIQx or total HAAs) or NAT2 genotype (Rapid versus Slow or Intermediate). This study suggests that the genomic region around ARNT rs12410394 may harbor variants associated with CRC.
动物实验涉及化学致癌物，如多环芳烃（PAHs）和杂环芳香胺（HAAs），这些物质可能导致结直肠癌（CRC）的发生。然而，由于这些化合物在个体内的生物活化存在差异，流行病学证据仍然不一致。我们在日裔美国人、欧裔美国人和夏威夷原住民中进行了结直肠腺瘤（914 例病例，1185 例对照）和结直肠癌（496 例病例，607 例对照）的病例对照研究，以调查通过测序鉴定的 PAH 和 HAA 生物活化途径（CYP1A1、CYP1A2、CYP1B1、AHR 和 ARNT）中的遗传变异与结直肠肿瘤风险的关联，以及它们与吸烟和红肉及 HAAs 摄入量的相互作用。ARNT rs12410394 的 A 等位基因与 CRC 呈显著负相关[GG、AG 和 AA 基因型的比值比（ORs）和 95%置信区间（CIs）：1.00、0.66（0.48-0.89）、0.54（0.37-0.78），P（趋势）=0.0008]，经过多次比较调整。CYP1A2 rs11072508 与 CRC 呈边缘显著相关，每个 T 等位基因与降低的风险相关（OR：0.72，95%CI：0.58-0.88，P（趋势）=0.0017）。未发现不同种族/民族群体之间遗传效应存在异质性。此外，在调整了吸烟包年数、红肉或 HAAs（PhIP、MeIQx、Di-MeIQx 或总 HAAs）或 NAT2 基因型（快速与慢速或中间）的多重测试后，没有观察到遗传变异与这些因素之间的显著相互作用。这项研究表明，ARNT rs12410394 周围的基因组区域可能存在与 CRC 相关的变异。
