Ruwali Munindra, Khan Anwar Jamal, Shah Parag P, Singh Arvind Pratap, Pant Mohan C, Parmar Devendra
Developmental Toxicology Division, Indian Institute of Toxicology Research, CSIR, Lucknow-226 001, Uttar Pradesh, India.
Environ Mol Mutagen. 2009 Jul;50(6):473-82. doi: 10.1002/em.20488.
The present case-control study investigates the association of polymorphisms in cytochrome P450 2E1 (CYP2E1), involved in the metabolism of tobacco carcinogens and alcohol, with Head and Neck Squamous Cell Carcinoma (HNSCC). In addition, the interaction of CYP2E1 (CYP2E15B and CYP2E16) with other genetic factors (null genotype of glutathione-S-Transferase M1, GSTM1, X-Ray Repair Cross Complementing Group I, XRCC1 (Arg194Trp), and environmental risk factors such as alcohol and tobacco in modifying HNSCC risk were investigated. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a total of 350 male cases of HNSCC and an equal number of healthy male controls. Statistical analysis showed a significant increase in HNSCC risk in cases with variant genotypes of CYP2E15B (RsaI) (O.R. 3.44; 95% C.I. 1.45-8.14) and CYP2E16 (DraI) (O.R. 1.76; 95% C.I. 1.28-2.41). Haplotype analysis revealed that haplotype T-A was associated with a greater than 10-fold increase in risk for HNSCC. Our data also revealed a several fold increase in HNSCC risk in cases carrying a combination of variant genotypes of CYP2E1 with the null genotype of GSTM1 or XRCC1 variant genotypes. Alcohol or tobacco use (both smoking and chewing) were also found to interact with variant genotypes of CYP2E1 in significantly enhancing HNSCC risk. This increase in risk associated with an interaction of CYP2E1 genotypes with GSTM1 or XRCC1 or with tobacco and alcohol use demonstrates the importance of gene-gene and gene-environment interactions in the development of HNSCC.
本病例对照研究调查了参与烟草致癌物和酒精代谢的细胞色素P450 2E1（CYP2E1）基因多态性与头颈部鳞状细胞癌（HNSCC）之间的关联。此外，还研究了CYP2E1（CYP2E15B和CYP2E16）与其他遗传因素（谷胱甘肽-S-转移酶M1的无效基因型，GSTM1，X射线修复交叉互补组I，XRCC1（Arg194Trp））以及酒精和烟草等环境风险因素在改变HNSCC风险方面的相互作用。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析确定了总共350例男性HNSCC病例和数量相等的健康男性对照的基因型。统计分析表明，CYP2E15B（RsaI）变异基因型（比值比3.44；95%置信区间1.45 - 8.14）和CYP2E16（DraI）变异基因型（比值比1.76；95%置信区间1.28 - 2.41）的病例中HNSCC风险显著增加。单倍型分析显示单倍型T - A与HNSCC风险增加超过10倍相关。我们的数据还显示，携带CYP2E1变异基因型与GSTM1无效基因型或XRCC1变异基因型组合的病例中HNSCC风险增加了几倍。还发现饮酒或使用烟草（吸烟和咀嚼）与CYP2E1变异基因型相互作用，显著增加HNSCC风险。CYP2E1基因型与GSTM1或XRCC1相互作用或与烟草和酒精使用相关的风险增加表明了基因-基因和基因-环境相互作用在HNSCC发生发展中的重要性。
