Morton Lindsay M, Schenk Maryjean, Hein David W, Davis Scott, Zahm Shelia Hoar, Cozen Wendy, Cerhan James R, Hartge Patricia, Welch Robert, Chanock Stephen J, Rothman Nathaniel, Wang Sophia S
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland 20852, USA.
Pharmacogenet Genomics. 2006 Aug;16(8):537-45. doi: 10.1097/01.fpc.0000215071.59836.29.
Animal studies suggest that lymphomagenesis can be induced by exposure to carcinogenic aromatic and heterocyclic amines found in diet, cigarette smoke and the environment, but human epidemiologic investigations of these exogenous exposures have yielded conflicting results. As part of our evaluation of the role of aromatic and heterocyclic amines, which are metabolized by N-acetyltransferase (NAT) enzymes, in the etiology of non-Hodgkin lymphoma (NHL), we examined NHL risk in relation to genetic variation in NAT1 and NAT2 and exposure to cigarette smoke and dietary heterocyclic amines and mutagens. We genotyped 10 common single nucleotide polymorphisms (SNPs) in NAT1 and NAT2 among 1136 cases and 922 controls from a population-based case-control study in four geographical areas of the USA. Relative risk of NHL for NAT1 and NAT2 genotypes, NAT2 acetylation phenotype, and exposure to cigarette smoke and dietary heterocyclic amines and mutagens was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) derived from unconditional logistic regression models. We observed increased risk of NHL among individuals with the NAT1*10/*10 genotype compared with individuals with other NAT1 genotypes (OR = 1.60, 95% CI = 1.04-2.46, P = 0.03). We also observed increased NHL risk in a dose-dependent model among NAT2 intermediate- and rapid-acetylators compared with slow-acetylators, although only the trend was statistically significant (intermediate: OR = 1.18, 95% CI = 0.97-1.44, P = 0.1; rapid: OR = 1.43, 95% CI = 0.97-2.14, P = 0.07; P for linear trend = 0.03). Compared with non-smokers, NHL risk estimates for current cigarette smoking were increased only among NAT2 intermediate/rapid-acetylators (OR = 2.44, 95% CI = 1.15-5.20, P = 0.02). Our data provide evidence that NAT1 and NAT2 genotypes are associated with NHL risk and support a contributory role for carcinogenic aromatic and/or heterocyclic amines in the multi-factorial etiology of NHL.
动物研究表明，接触饮食、香烟烟雾和环境中存在的致癌性芳香胺和杂环胺可诱发淋巴瘤发生，但针对这些外源性暴露因素的人类流行病学调查结果却相互矛盾。作为我们对由N-乙酰转移酶（NAT）代谢的芳香胺和杂环胺在非霍奇金淋巴瘤（NHL）病因学中作用评估的一部分，我们研究了NHL风险与NAT1和NAT2基因变异以及香烟烟雾暴露、饮食中杂环胺和诱变剂之间的关系。我们对来自美国四个地理区域的一项基于人群的病例对照研究中的1136例病例和922例对照的NAT1和NAT2中的10个常见单核苷酸多态性（SNP）进行了基因分型。使用无条件逻辑回归模型得出的比值比（OR）和95%置信区间（CI）估计NAT1和NAT2基因型、NAT2乙酰化表型以及香烟烟雾暴露、饮食中杂环胺和诱变剂导致NHL的相对风险。我们观察到，与具有其他NAT1基因型的个体相比，携带NAT1*10/*10基因型的个体患NHL的风险增加（OR = 1.60，95% CI = 1.04 - 2.46，P = 0.03）。我们还观察到，与慢乙酰化者相比，在NAT2中速和快速乙酰化者中，NHL风险在剂量依赖模型中增加，尽管只有趋势具有统计学意义（中速：OR = 1.18，95% CI = 0.97 - 1.44，P = 0.1；快速：OR = 1.43，95% CI = 0.97 - 2.14，P = 0.07；线性趋势P = 0.03）。与不吸烟者相比，仅在NAT2中速/快速乙酰化者中，当前吸烟导致的NHL风险估计值增加（OR = 2.44，95% CI = 1.15 - 5.20，P = 0.02）。我们的数据提供了证据表明NAT1和NAT2基因型与NHL风险相关，并支持致癌性芳香胺和/或杂环胺在NHL多因素病因学中的促成作用。
