Girard Hugo, Butler Lesley M, Villeneuve Lyne, Millikan Robert C, Sinha Rashmi, Sandler Robert S, Guillemette Chantal
Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2 Québec, Canada.
Mutat Res. 2008 Sep 26;644(1-2):56-63. doi: 10.1016/j.mrfmmm.2008.07.002. Epub 2008 Jul 16.
Glucuronidation by the UDP-glucuronosyltransferase enzymes (UGTs) is one of the primary detoxification pathways of dietary heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). In a population-based case-control study of 537 cases and 866 controls, we investigated whether colon cancer was associated with genetic variations in UGT1A1 and UGT1A9 genes and we determined if those variations modify the association between colon cancer and dietary HCA and PAH exposure. We measured functional UGT1A1 polymorphisms at positions -53 (28; A(TA)6TAA to A(TA)7TAA), -3156 (G>A), -3279 (T>G) and the UGT1A9-275(T>A) polymorphism, and found no association with colon cancer overall. However, when stratified by race, the UGT1A1-3279 GG/TG intermediate/low activity genotypes were associated with an increased risk of colon cancer (odds ratio (OR)=1.5, 95% confidence interval (CI)=1.1-2.0) in Caucasians. This finding is also supported by haplotype analyses where the UGT1A1-3279G-allele-bearing haplotype is overrepresented in case group. Overall, UGT1A1-53 and -3156 genotypes modified the association between dietary benzo(a)pyrene (BaP) and colon cancer (P for interaction=0.02 and 0.03, respectively). The strongest association was observed for those with <7.7 ng/day BaP exposure and the low activity genotypes, for both UGT1A1 28/28 (OR=1.8, 95% CI=1.1-2.9) and -3156AA (OR=1.7, 95% CI=1.0-3.0), compared to >or=7.7 ng/day and combined high/intermediate genotypes. These data support a hypothesis that UGTs modify the association between meat-derived PAH exposure and colon cancer by their role in the elimination of dietary carcinogens.
由尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）介导的葡萄糖醛酸化作用是膳食杂环胺（HCAs）和多环芳烃（PAHs）的主要解毒途径之一。在一项基于人群的病例对照研究中，我们纳入了537例病例和866例对照，调查结肠癌是否与UGT1A1和UGT1A9基因的遗传变异相关，并确定这些变异是否会改变结肠癌与膳食中HCA和PAH暴露之间的关联。我们检测了位于-53（28；A(TA)6TAA变为A(TA)7TAA）、-3156（G>A）、-3279（T>G）位置的功能性UGT1A1多态性以及UGT1A9-275(T>A)多态性，发现总体上与结肠癌无关联。然而，按种族分层后，在白种人中，UGT1A1-3279 GG/TG中等/低活性基因型与结肠癌风险增加相关（优势比（OR）=1.5，95%置信区间（CI）=1.1 - 2.0）。单倍型分析也支持这一发现，即携带UGT1A1-3279G等位基因的单倍型在病例组中过度存在。总体而言，UGT1A1-53和-3156基因型改变了膳食苯并(a)芘（BaP）与结肠癌之间的关联（交互作用P值分别为0.02和0.03）。对于BaP暴露<7.7 ng/天且为低活性基因型的个体，无论是UGT1A1 28/28（OR=1.8，95% CI=1.1 - 2.9）还是-3156AA（OR=1.7，95% CI=1.0 - 3.0），与BaP暴露≥7.7 ng/天且为高/中等活性基因型组合的个体相比，观察到最强的关联。这些数据支持了一个假说，即UGTs通过其在消除膳食致癌物中的作用，改变了肉类来源的PAH暴露与结肠癌之间的关联。
