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I期和II期代谢基因多态性与结直肠癌风险的综合分析。

A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of colorectal cancer.

作者信息

Landi Stefano, Gemignani Federica, Moreno Victor, Gioia-Patricola Lydie, Chabrier Amélie, Guino Elisabeth, Navarro Matilde, de Oca Javier, Capellà Gabriel, Canzian Federico

机构信息

Genetica, Dip. Scienze Uomo e Ambiente, University of Pisa, Italy.

出版信息

Pharmacogenet Genomics. 2005 Aug;15(8):535-46. doi: 10.1097/01.fpc.0000165904.48994.3d.

Abstract

OBJECTIVES

Sporadic colorectal cancer (CRC) is considered a multifactorial disease where multiple exposures interact with the individual genetic background resulting in risk modulation. We performed an association study aimed to investigate the role of single nucleotide polymorphisms (SNPs) within genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2D6, CYP2E1, CYP2C9, CYP2C19, CYP3A4, ADH2, EPHX1) and phase II of the xenobiotic metabolism (ALDH2, COMT, GSTA2, GSTA4, GSTM1, GSTM3, GSTP1, GSTT2, MTHFR, NAT1, NAT2, NQO1, MnSOD2, SULT1A1, TPMT).

METHODS

We genotyped 377 cases and 326 controls, by use of an oligonucleotide micro-array and the arrayed primer extension technique (APEX).

RESULTS

N-acetyl-transferase 1 'rapid' phenotype and CYP1A2 -164C>A carriers were associated with increased risk of CRC, confirming data reported in previous studies. Interestingly, homozygotes for allele 48G within CYP1B1, a variant with an increased activity towards several substrates including sex hormones, were at increased risk (OR=2.81, 95% CI 1.32-5.99). Moreover, CYP1A1 SNPs T461N and -1738A>C were associated with a reduced risk of cancer (OR=0.52; 95% CI 0.31-0.88 and OR=0.69, 95% CI 0.50-0.94 for carriers, respectively).

CONCLUSIONS

The present data suggest a role for CYP1B1 and CYP1A1 as new candidate genes in the etiology of CRC and confirm the carcinogenic role of aromatic amines metabolism for colorectum.

摘要

目的

散发性结直肠癌(CRC)被认为是一种多因素疾病,多种暴露因素与个体遗传背景相互作用,从而调节发病风险。我们开展了一项关联研究,旨在调查参与异生物质代谢的Ⅰ相(CYP1A1、CYP1A2、CYP1B1、CYP2A6、CYP2D6、CYP2E1、CYP2C9、CYP2C19、CYP3A4、ADH2、EPHX1)和Ⅱ相(ALDH2、COMT、GSTA2、GSTA4、GSTM1、GSTM3、GSTP1、GSTT2、MTHFR、NAT1、NAT2、NQO1、MnSOD2、SULT1A1、TPMT)基因内单核苷酸多态性(SNP)的作用。

方法

我们使用寡核苷酸微阵列和引物延伸技术(APEX)对377例病例和326例对照进行基因分型。

结果

N-乙酰转移酶1的“快速”表型和CYP1A2 -164C>A携带者与CRC风险增加相关,证实了先前研究报告的数据。有趣的是,CYP1B1基因内48G等位基因的纯合子,该变体对包括性激素在内的几种底物活性增加,其风险增加(OR=2.81,95%CI 1.32-5.99)。此外,CYP1A1的SNP T461N和-1738A>C与癌症风险降低相关(携带者的OR分别为0.52;95%CI 0.31-0.88和OR=0.69,95%CI 0.50-0.94)。

结论

目前的数据表明CYP1B1和CYP1A1作为CRC病因学中的新候选基因发挥作用,并证实了芳香胺代谢对结肠的致癌作用。

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