Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk
Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk
复制标题
DOI：
10.1053/j.gastro.2009.07.070
复制
发表时间：
2009-11-01
期刊：
影响因子：
29.4
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
--
作者：
Cui, Ri;Kamatani, Yoichiro;Matsuda, Koichi
背景与目的：食管鳞状细胞癌（ESCC）在亚洲人群中普遍存在，其发病率和死亡率存在明显的区域差异。ESCC患者的预后非常差，但早期发现ESCC可改善临床结局。因此，识别影响ESCC发展的流行病学因素将有助于预防和/或早期发现该疾病。方法：我们对1070例日本ESCC病例和2836例对照进行了两步全基因组关联研究和随后的复制分析。我们还使用逻辑回归分析来估计基因-基因和基因-环境相互作用的影响。研究结果：我们确定了ESCC与4 q21 -23和12 q24区域的显著相关性，其中包括先前显示与ESCC易感性相关的ADH 1B（rs 1229984，P = 6.76 x 10（-35））和ALDH 2（rs671，P = 3.68 x 10（-68））的非同义单核苷酸多态性（SNP）。多因素Logistic回归分析显示SNP rs671、rs 1229984、饮酒和吸烟是ESCC的独立危险因素（优势比分别为1.66、1.85、1.92和1.79）。此外，同时具有遗传和生活方式相关风险因素的个体患ESCC的风险比没有这两者的人高出近190倍。结论：我们发现2个已知的功能变异体参与了酒精和烟草副产品的代谢，是日本人群中ESCC发展的最重要的危险因素。携带这两种风险基因型的个体具有较高的ESCC基线风险，其显著增加了2种生活方式风险因素。
BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease. METHODS: We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions. RESULTS: We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 x 10(-35)) and ALDH2 (rs671, P = 3.68 x 10(-68)) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these. CONCLUSIONS: We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.