Chan Andrew T, Tranah Gregory J, Giovannucci Edward L, Hunter David J, Fuchs Charles S
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, GRJ-722, Boston, MA 02114, USA.
J Natl Cancer Inst. 2005 Mar 16;97(6):457-60. doi: 10.1093/jnci/dji066.
Genetic variation in the uridine diphosphate glucuronosyltransferase 1A6 (UGT1A6) enzyme is associated with impaired metabolism of aspirin. To determine whether polymorphisms in the UGT1A6 enzyme modulate the protective benefit of regular aspirin use on colorectal adenoma, we conducted a prospective, nested case-control study of 1062 women who provided blood specimens and detailed data on aspirin use before undergoing lower endoscopy. All statistical tests were two sided. Although UGT1A6 genotype was not associated with overall adenoma risk (multivariable odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.85 to 1.41), functional variant genotypes statistically significantly modified the effect of aspirin on adenoma (P(interaction) = .02). Among the 616 women with variant genotypes, regular use of aspirin (two or more standard tablets per week) was associated with a decreased risk of adenoma (multivariable OR for adenoma = 0.66 [95% CI = 0.45 to 0.95], OR = 0.63 [95% CI = 0.43 to 0.91] for 0.5-7 standard tablets per week and OR = 0.41 [95% CI = 0.24 to 0.71] for more than 7 tablets per week; P(trend) = .001). In contrast, among women with wild-type genotypes, regular aspirin use was not associated with a reduced risk nor did they obtain any additional benefit with higher doses (P(trend) = .50). These results were consistent among women with advanced adenomas (P(interaction) = .003). Thus, functional polymorphisms in the UGT1A6 enzyme statistically significantly modify the effect of aspirin on colorectal neoplasia, and certain subsets of the population, defined by genotype, may obtain differential benefit from aspirin chemoprevention.
尿苷二磷酸葡萄糖醛酸基转移酶1A6（UGT1A6）的基因变异与阿司匹林代谢受损有关。为了确定UGT1A6酶的多态性是否调节常规使用阿司匹林对结肠直肠腺瘤的保护作用，我们对1062名女性进行了一项前瞻性巢式病例对照研究，这些女性在接受低位内镜检查前提供了血液样本和关于阿司匹林使用的详细数据。所有统计检验均为双侧检验。虽然UGT1A6基因型与总体腺瘤风险无关（多变量优势比[OR]=1.10，95%置信区间[CI]=0.85至1.41），但功能变异基因型在统计学上显著改变了阿司匹林对腺瘤的作用（P（交互作用）=0.02）。在616名具有变异基因型的女性中，常规使用阿司匹林（每周两片或更多标准片）与腺瘤风险降低相关（腺瘤的多变量OR=0.66[95%CI=0.45至0.95]，每周0.5 - 7片标准片的OR=0.63[95%CI=0.43至0.91]，每周超过7片的OR=0.41[95%CI=0.24至0.71]；P（趋势）=0.001）。相比之下，在具有野生型基因型的女性中，常规使用阿司匹林与风险降低无关，高剂量使用也未带来任何额外益处（P（趋势）=0.50）。这些结果在患有晚期腺瘤的女性中是一致的（P（交互作用）=0.003）。因此，UGT1A6酶的功能多态性在统计学上显著改变了阿司匹林对结肠直肠肿瘤的作用，并且由基因型定义的某些人群亚组可能从阿司匹林化学预防中获得不同的益处。
