饮酒量与乙醛脱氢酶 (ALDH2) 和醇脱氢酶 (ADH) 的功能遗传多态性相互作用，增加食管鳞状细胞癌风险。

Alcohol Intake Interacts with Functional Genetic Polymorphisms of Aldehyde Dehydrogenase (ALDH2) and Alcohol Dehydrogenase (ADH) to Increase Esophageal Squamous Cell Cancer Risk.

机构信息

State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, People's Republic of China; Department of Epidemiology, School of Public Health, Fudan University, Shanghai, People's Republic of China; Fudan University Taizhou Institute of Health Sciences, Taizhou, People's Republic of China.

State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, People's Republic of China; Fudan University Taizhou Institute of Health Sciences, Taizhou, People's Republic of China.

出版信息

J Thorac Oncol. 2019 Apr;14(4):712-725. doi: 10.1016/j.jtho.2018.12.023. Epub 2019 Jan 9.

DOI:10.1016/j.jtho.2018.12.023

PMID:30639619

Abstract

INTRODUCTION

Studies have reported alcohol consumption and genetic variants as major contributing factors for esophageal squamous cell carcinoma (ESCC). However, the complicated interactions between alcohol and genetic factors involved in alcohol metabolism have not been well elucidated with respect to augmented risk of ESCC.

METHODS

We performed a large population-based case-control study in a Chinese city with a high ESCC incidence by enrolling 1190 case patients and 1883 controls. We integrated candidate single-nucleotide polymorphism data, detailed alcohol consumption records, gene-alcohol interactions, and single-nucleotide polymorphism functional information to untangle the complicated relationship between alcohol, variants of genes encoding alcohol metabolism enzymes, and ESCC risk. The gene-alcohol interaction was tested by including their product term in a multivariable logistic regression model. Synergy index and ratio of ORs were calculated to assess interaction on additive and multiplicative scale, respectively.

RESULTS

We confirmed two ESCC susceptibility loci, rs671 in aldehyde dehydrogenase 2 family member gene (ALDH2) and rs1042026 in alcohol dehydrogenase 1B (class I), beta polypeptide gene (ADH1B), that significantly altered alcohol consumption behavior and subsequently modified the association between alcohol consumption and ESCC risk. The rs671(A) allele was associated with ESCC risk in alcohol drinkers (adjusted odds ratio =1.98, 95% confidence interval [CI]: 1.51-2.60) but not in nondrinkers. Healthy individuals who carry different ALDH2 and ADH1B genotypes exhibit diversified drinking behavior, with the proportion of drinkers varying between 23.7% and 54.3%. Among individuals with a fast ethanol oxidization rate, we observed a strong interaction between heavy alcohol consumption and ethanal oxidization rate on both the additive scale (synergy index 4.80 [95% CI: 1.82-12.68]) and the multiplicative scale (ratio of ORs 2.93, 95% CI: 1.39-6.35).

CONCLUSIONS

Our observation highlights the need for preventing excessive use of alcohol, especially in individuals harboring active alcohol dehyrogenase and inactive ALDH2 variants.

摘要

简介

已有研究表明，饮酒和与酒精代谢相关的基因变异是导致食管鳞状细胞癌（ESCC）的主要因素。然而，酒精与遗传因素之间复杂的相互作用，以及其对 ESCC 风险的影响，仍未得到充分阐明。

方法

我们在中国一个 ESCC 高发城市进行了一项大型基于人群的病例对照研究，共纳入 1190 例病例和 1883 例对照。我们整合了候选单核苷酸多态性数据、详细的饮酒记录、基因-酒精相互作用以及单核苷酸多态性功能信息，以厘清酒精、编码酒精代谢酶的基因变异与 ESCC 风险之间复杂的关系。通过在多变量逻辑回归模型中包含它们的乘积项来检验基因-酒精相互作用。分别采用协同指数和比值比来评估加性和乘法尺度上的相互作用。

结果

我们证实了两个 ESCC 易感基因座，即乙醛脱氢酶 2 家族成员基因（ALDH2）中的 rs671 和 1 类酒精脱氢酶β多肽基因（ADH1B）中的 rs1042026，它们显著改变了饮酒行为，进而改变了饮酒与 ESCC 风险之间的关联。rs671（A）等位基因与饮酒者的 ESCC 风险相关（校正后的比值比=1.98，95%置信区间[CI]：1.51-2.60），但与非饮酒者无关。携带不同 ALDH2 和 ADH1B 基因型的健康个体表现出多样化的饮酒行为，饮酒者的比例在 23.7%至 54.3%之间变化。在具有快速乙醇氧化率的个体中，我们观察到在加性尺度（协同指数 4.80[95%CI：1.82-12.68]）和乘法尺度（比值比 2.93，95%CI：1.39-6.35）上，重度饮酒和乙二醛氧化率之间存在强烈的相互作用。