Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk

酒精摄入和酒精使用障碍与癌症风险的遗传因果关系

• 批准号: 10218720
• 负责人: Hang Zhou
• 金额: $ 18.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218720
• 关键词: Acetaldehyde; Acetates; Aerodigestive Tract; African; Alcohol consumption; Alcohol dehydrogenase; Alcoholic Beverages; Alcohols; American; Asians; Beverages; Biological; Biological Process; Body mass index; Cause of Death; Colon Carcinoma; Colorectal Cancer; DNA Methylation; Data; Development; Ensure; Epidemiology; Ethanol; Etiology; European; Gene Expression; Genes; Genetic; Genetic Risk; Genetic study; Genotype; Human; Individual; International Agency for Research on Cancer; Latino; Lead; Light; Link; Linkage Disequilibrium; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of liver; Malignant neoplasm of pharynx; Measures; Mediating; Mediation; Mediator of activation protein; Mendelian randomization; Methods; Methylation; Modeling; Molecular; Oral cavity; Oropharyngeal; Outcome; Oxides; Pathway interactions; Play; Population; Prevention; Prevention strategy; Proteins; Proteomics; Quantitative Trait Loci; Regulation; Role; Sample Size; Sampling; Series; Smoking; Testing; Upper aerodigestive tract cancer; Variant; alcohol abuse therapy; alcohol availability; alcohol effect; alcohol related gene; alcohol use disorder; aldehyde dehydrogenases; base; cancer risk; cancer type; carcinogenicity; cohort; disability; disorder prevention; epigenetic marker; genetic variant; genome wide association study; genome-wide; improved; instrument; interest; large scale data; malignant breast neoplasm; metabolomics; pleiotropism; power analysis; risk variant; statistics; trait; treatment strategy

Project Summary/Abstract Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk Alcohol use and alcohol use disorder (AUD) are among the leading causes of death and disability worldwide. Ethanol, i.e. beverage alcohol, is mainly oxidized by alcohol dehydrogenases (several ADH genes) to acetaldehyde, which is then detoxified to acetate by aldehyde dehydrogenases (mainly ALDH2). Acetaldehyde and alcoholic beverages are classified as carcinogenic to humans by the International Agency for Research on Cancer. Cumulative epidemiological evidence has shown that alcohol consumption is associated with the development of cancers including upper aerodigestive tract, breast, liver and colorectal cancer; 5.5% of all cancers are attributable to alcohol, totaling 770,000 cases annually. A better understanding of the molecular basis by which alcohol increases cancer risk could lead to improved treatment and preventative strategies. Genome-wide association studies (GWASs) have identified risk genes for alcohol-related traits and cancers, and some genes show pleiotropic effects on both. However, the genetic relationship between alcohol and cancers remains largely unclear. Recently, large GWASs have been conducted on alcohol-related traits and cancers, provided opportunities to answer the above question. The proposed study will take advantage of large scale genetic data in multiple populations to discover genetic risk variants playing roles in both alcohol-related traits (alcohol use and AUD) and alcohol-associated cancers, study the genetic correlations among them, and investigate the genetic causality between alcohol traits and cancers using Mendelian Randomization (MR). Additionally, by integrating summary data regarding large-scale gene expression, eQTL, mQTL, metabolomic QTL and proteomic QTLs into 2-step MR, we aim to identify genes whose expression levels are associated with alcohol-associated cancer variation, identify regulatory and epigenetic markers that mediate the relationship between alcohol and cancers, and identify the relevant pathway mechanisms that involve acetaldehyde and, potentially, other metabolites. This study will help us to understand better the genetic mechanisms that underlie the relationship between alcohol traits and alcohol-associated cancers, with the potential to improve disease prevention and treatment strategies.

项目总结/文摘