Cigarette smoking, N-acetyltransferase genes and the risk of advanced colorectal adenoma
Cigarette smoking, N-acetyltransferase genes and the risk of advanced colorectal adenoma
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DOI：
10.2217/14622416.7.6.819
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发表时间：
2006-09-01
期刊：
影响因子：
2.1
通讯作者：
Hayes, Richard B.
中科院分区：
文献类型：
--
作者：
Moslehi, Roxana;Chatterjee, Nilanjan;Hayes, Richard B.
背景：吸烟与结直肠腺瘤（一种结直肠癌前体）的风险增加有关。N-乙酰转移酶NAT 1和NAT 2是参与香烟烟雾中芳香胺致癌物代谢的重要酶。我们的兴趣是在NAT 1和NAT 2基因内的多态性，通过影响烟草烟雾衍生的致癌物的代谢活化和清除来影响烟草-结直肠肿瘤的关系。研究方法：在前列腺、肺、结直肠和卵巢（PLCO）癌筛查试验中，我们比较了772例左侧晚期腺瘤患者和777例性别和年龄匹配的对照组的NAT 1和NAT 2基因变异分布。分配个体NAT 1和NAT 2双倍型，并推导出NAT 2乙酰化表型。结果如下：与不吸烟者相比，近期吸烟者（目前吸烟者或戒烟不到10年的人）（比值比[OR] = 2.3，95%置信区间[CI]：1.7-3.1）和每天吸烟超过20支的人（OR = 1.7，95% CI：1.3-2.2）中晚期结直肠腺瘤的风险显著增加。总体而言，风险随着NAT 2表型活性的增加而降低（0：缓慢，1：中等，2：快速）（OR趋势：0.8; 95% CI：0.7-1.0，p趋势= 0.04）。当按吸烟状态分层时，在近期吸烟者中观察到显著的表型相关趋势（OR趋势= 0.4，95% CI：0.3-0.7，p趋势< 0.001）（p-相互作用= 0.02），但在既往或非吸烟者中未观察到。与吸烟者风险较低最密切相关的二倍型是NAT 2 *4/* 5 B（OR = 0.3，95%CI：0.1-0.8，p = 0.01）和NAT 2 *4/*4（OR = 0.2，95%CI：0.04-0.7，p = 0.02），分别归类为中间乙酰化者和快速乙酰化者。一种NAT 1双倍型NAT 1 *4/*10（OR = 0.5，95%CI：0.3-0.9，p = 0.03）也与吸烟者风险降低相关。结论：我们的研究表明，与慢乙酰化表型相关的NAT 2基因变异体更容易受到吸烟对腺瘤风险的影响，为疾病预防提供了线索。
Background: Cigarette use is associated with greater risk for colorectal adenoma, a colorectal cancer precursor. N-acetyltransf erases, NAT1 and NAT2, are important enzymes involved in the metabolism of aromatic amine carcinogens present in cigarette smoke. Our interest is in the polymorphisms within the NAT1 and NAT2 genes that influence the tobacco-colorectal tumor relationship by impacting on the metabolic activation and cletoxification of tobacco smoke-derived carcinogens. Methods: In the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, we compared NAT1 and NAT2 gene variant distributions for 772 cases with left-sided advanced adenoma and 777 gender and age-matched controls. Individual NAT1 and NAT2 diplotypes were assigned and NAT2 acetylator phenotypes were derived. Results: Risks for advanced colorectal adenoma were significantly increased among recent smokers (current smokers or those who quit less than 10 years ago) (odds ratio [OR] = 2.3, 95% confidence interval [Cl]: 1.7-3.1) and among those who smoked more than 20 cigarettes per day (OR = 1.7, 95% Cl: 1.3-2.2), compared with nonsmokers. Risk decreased with increasing NAT2 phenotypic activity (0: slow, 1: intermediate, and 2: rapid) (OR trend: 0.8; 95% Cl: 0.7-1.0, p-trend = 0.04) overall. When stratified by smoking status, significant phenotype-associated trends were observed among recent smokers (OR trend = 0.4, 95% Cl: 0.3-0.7, p trend < 0.001) (p-interaction = 0.02), but not among past or nonsmokers. Diplotypes most strongly associated with lower risks in smokers were NAT2*4/*5B (OR = 0.3, 95% Cl: 0.1-0.8, p = 0.01) and NAT2*4/*4 (OR = 0.2, 95% Cl: 0.04-0.7, p = 0.02), categorized as intermediate and rapid acetylators, respectively. One NAT1 diplotype, NAT1*4/*10 (OR = 0.5, 95% Cl: 0.3-0.9, p = 0.03), was also associated with a decreased risk in smokers. Conclusions: Our study indicated that NAT2 gene variants associated with a slow acetylator phenotype were more susceptible to the effects of tobacco smoking with respect to adenoma risk, providing leads for disease prevention.