GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population
GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population
复制标题
DOI：
10.1002/ijc.20157
复制
发表时间：
2004-07-01
影响因子：
6.4
通讯作者：
Porru, S
中科院分区：
文献类型：
--
作者：
Hung, RJ;Boffetta, P;Porru, S
吸烟和职业是通过接触多环芳烃 (PAH) 和芳香胺而导致膀胱癌的主要危险因素。谷胱甘肽 s-转移酶 (GST) M1、T1 和 P1 参与 PAH 反应性代谢物的解毒。两种 N-乙酰转移酶同工酶 NAT2 和 NAT1 在催化芳香胺的 N-乙酰化和 O-乙酰化中起主要作用。细胞色素 P450 1B1 (CYP1B1) 和磺基转移酶 1A1 (SULT1A1) 也参与 PAH 和芳香胺的代谢。据推测，这些代谢酶的遗传多态性对个体对膀胱癌的易感性有影响，特别是通过与相关环境暴露的相互作用。意大利北部布雷西亚的一项以医院为基础的男性病例对照研究招募了 1997 年至 2000 年间的 201 名发病病例和 214 名对照组。职业暴露由职业医生盲目编码。采用PCR-RFLP方法进行多态性基因分型。应用无条件多变量逻辑回归来模拟遗传多态性与膀胱癌风险之间的关联。评估了发病年龄、吸烟和职业接触多环芳烃和芳香胺的影响。我们还对遗传因素之间的相互作用进行了分析。 GSTM1 和 GSTT1 无效基因型与膀胱癌风险增加相关，比值比 (OR) 分别为 1.69（95% 置信区间 [CI] = 1.11-2.56）和 1.74（95% CI = 1.02-2.95）。 GSTM1 null 的影响在重度吸烟者中尤其明显，并且与职业接触芳香胺有综合影响（OR = 2.77，95% CI = 1.08-7.10）。将 GSTM1 和 T1 活性正常的受试者与具有一种（OR = 1.82，95% CI = 1.16-2.85）或两种无效基因型（OR = 2.58，95% CI = 1.27-5.23）的受试者进行比较，我们观察到癌症风险增加的趋势（p 值 < 0.01）。 NAT2慢乙酰化与膀胱癌风险略有增加相关（OR = 1.50，95% CI = 0.99-2.27），与职业接触芳香胺的联合效应的OR为3.26（95% CI = 1.06-9.95）。 SULT1A1 Arg213His 多态性显示出边际保护作用。这些发现表明个体对膀胱癌的易感性可能受到 GSTM1、GSTT1 和 NAT2 多态性的调节。 (C) 2004 Wiley-Liss, Inc.
Tobacco smoking and occupation are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. Glutathione s-transferase (GST) M1, T1 and P1 are involved in the detoxification of PAH reactive metabolites. Two N-acetyltransferase isozymes, NAT2 and NAT1, have major roles in catalyzing the N-acetylation and O-acetylation of aromatic amines. Cytochrome P450 1B1 (CYP1B1) and sulfotransferase 1A1 (SULT1A1) are also involved in the metabolism of PAHs and aromatic amines. It is hypothesized that the genetic polymorphisms of these metabolic enzymes have an effect on the individual susceptibility to bladder cancer in particular by interacting with relevant environmental exposures. A hospital-based case-control study among men in Brescia, Northern Italy recruited 201 incidence cases and 214 controls from 1997-2000. Occupational exposures were blindly coded by occupational physicians. Genotyping of polymorphisms were carried out with PCR-RFLP method. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk. Effect modifications by age of onset, smoking and occupational exposures to PAHs and aromatic amines were evaluated. We also conducted an analysis of interaction between genetic factors. GSTM1 and GSTT1 null genotype were associated with an increased risk of bladder cancer with an odds ratio (OR) of 1.69 (95% confidence interval [CI] = 1.11-2.56) and 1.74 (95% CI = 1.02-2.95), respectively. The effect of GSTM1 null was seen particularly in heavy smokers, and there was a combined effect with occupational exposure of aromatic amines (OR = 2.77, 95% CI = 1.08-7.10). We observed a trend (p-value < 0.01) of increasing cancer risk comparing subjects with normal GSTM1 and T1 activity to subjects with one (OR = 1.82, 95% CI = 1.16-2.85) or both null genotypes (OR = 2.58, 95% CI = 1.27-5.23). NAT2 slow acetylator was associated with marginally increased risk of bladder cancer (OR = 1.50, 95% CI = 0.99-2.27), and the OR for the joint effect with occupational exposure of aromatic amines was 3.26 (95% CI = 1.06-9.95). SULT1A1 Arg213His polymorphism showed a marginal protective effect. These findings suggest that individual susceptibility to bladder cancer may be modulated by GSTM1, GSTT1 and NAT2 polymorphisms. (C) 2004 Wiley-Liss, Inc.