A case-control study of hepatocellular carcinoma in relation to interaction between genetic polymorphisms of drug metabolizing enzymes and drinking/smoking habits

肝细胞癌药物代谢酶基因多态性与饮酒/吸烟习惯相互作用的病例对照研究

• 批准号: 11670344
• 负责人: TANAKA Keitaro
• 金额: $ 0.32万
• 依托单位: Saga Medical School (2000-2001)Kyushu University (1999)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670344/
• 关键词: hepatocellular carcinoma; case-control study; genetic polymorphism; cytochrome P450; N-acetyltransferase; alcohol; smoking; 喫煙

Although hepatitis C (HG) and hepatitis B (HB) viruses represent two major causative agents of hepatocellular carcinoma (HCC) in Japan, potential modifying effects of genotypes of drug metabolizing enzymes, such as cytochrome P450 (CYP) and N-acetyltransferase (NAT), on HCC risk have been suggested. We examined whether CYP2E1 and NAT2 polymorphisms were associated with HCC, and whether each polymorphism interacted with drinking and smoking habits in hepatocarcinogenesis. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (CYP2E 1 : Rsal polymorphism in the 5'-flanking region ; NAT2 : Asp718/BamHI/TaqI polymorphism in the coding region near the 3' end) on peripheral leukocyte DNA from 41 incident cases with HCC (71 % male, 80 % HC+, 17 % HB+) and 104 hospital controls with various minor disorders (71% male, 8% HC+, 2% HB+). The cl/cl, cl/c2, and c2/c2 genotypes ofCYP2E1 were found in 73 %, 22 %, and 5 % of cases, as compared with 63 %, 35 %, and 2 % of controls; theodds ratio (OR) for the cl/cl genotype vs. others was 1.6 (95 %CI 0.7 - 3.5). The risk for the cl/cl genotype was elevated substantially among males with heavy drinking history (OR = 9.0), but not among males without such a history (OR = 0.9, P for interaction = 0.09). Similar interaction between the cl/cl genotype and current smoking was observed (Ors: 4.3 vs. 0.8). Overall, NAT2 polymorphism was not associated with HCC risk, yet the rapid acetylator genotype tended to show higher risk among current smokers (OR = 1.9) than among never/past smokers (OR = 0.8). CYP2E1 and NAT2 polymorphisms may play additional roles in alcohol- and smoking-related hepatocarcinogenesis.

虽然丙型肝炎病毒（HG）和B肝炎病毒（HB）是日本肝细胞癌（HCC）的两个主要病原体，但已提出药物代谢酶（如细胞色素P450（CYP）和N-乙酰转移酶（NAT））基因型对HCC风险的潜在修饰作用。我们研究了CYP 2 E1和NAT 2多态性是否与HCC相关，以及每个多态性是否与肝癌发生中的饮酒和吸烟习惯相互作用。采用聚合酶链反应-限制性片段长度多态性进行基因分型（CYP 2 E1：5 '侧翼区的Rsal多态性; NAT 2：41例原发性肝癌患者外周血白细胞DNA编码区Asp 718/BamHI/TaqI多态性分析（71%男性，80% HC+，17% HB+）和104名患有各种轻微疾病的医院对照（71%男性，8% HC+，2% HB+）。CYP 2 E1基因cl/cl、cl/c2和c2/c2基因型分别占73%、22%和5%，而对照组分别为63%、35%和2%，cl/cl基因型与其他基因型的比值比（OR）为1.6（95%CI 0.7 - 3.5）。在有大量饮酒史的男性中，cl/cl基因型的风险显著升高（OR = 9.0），但在无此类病史的男性中则无此风险（OR = 0.9，P = 0.09）。观察到cl/cl基因型和当前吸烟之间的类似相互作用（OR：4.3 vs. 0.8）。总体而言，NAT 2多态性与HCC风险无关，但快速乙酰化基因型倾向于显示当前吸烟者（OR = 1.9）比从未/过去吸烟者（OR = 0.8）的风险更高。CYP 2 E1和NAT 2多态性可能在酒精和吸烟相关的肝癌发生中发挥额外的作用。