Chen Suo1, Yajun Yang2, Ziyu Yuan2, Tiejun Zhang3, Xiaorong Yang4, Tao Qing2, Pei Gao5, Leming Shi5, Min Fan6, Hongwei Cheng7, Ming Lu8, Li Jin9, Xingdong Chen10, Weimin Ye11. 1. 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. 2. 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. 3. Department of Epidemiology, School of Public Health, Fudan University, Shanghai, People's Republic of China. 4. Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, People's Republic of China. 5. 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. 6. Taixing Disease Control and Prevention Center, Taizhou, People's Republic of China. 7. Taixing People's Hospital, Taizhou, People's Republic of China. 8. Fudan University Taizhou Institute of Health Sciences, Taizhou, People's Republic of China; Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, People's Republic of China. 9. 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; Human Phenome Institute, Fudan University, Shanghai, People's Republic of China. 10. 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; Human Phenome Institute, Fudan University, Shanghai, People's Republic of China. Electronic address: xingdongchen@fudan.edu.cn. 11. Fudan University Taizhou Institute of Health Sciences, Taizhou, People's Republic of China; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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.
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.