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.

项目概要/摘要 酒精摄入和酒精使用障碍与癌症风险的遗传因果关系 饮酒和酒精使用障碍 (AUD) 是全球死亡和残疾的主要原因之一。 乙醇，即饮料酒精，主要被乙醇脱氢酶（几个ADH基因）氧化成 乙醛，然后被乙醛脱氢酶（主要是 ALDH2）解毒成乙酸。乙醛 酒精饮料被国际研究机构列为人类致癌物 癌症。累积的流行病学证据表明，饮酒与 癌症的发展，包括上呼吸消化道癌、乳腺癌、肝癌和结直肠癌；占总数的5.5% 每年因酒精导致癌症的病例总数为 770,000 例。更好地了解分子 酒精增加癌症风险的基础可能会导致治疗和预防策略的改进。 全基因组关联研究（GWAS）已经确定了与酒精相关的特征和癌症的风险基因， 有些基因对两者都表现出多效性。然而，酒精与遗传之间的关系 癌症在很大程度上仍不清楚。最近，大型 GWAS 已针对酒精相关特征和 癌症提供了回答上述问题的机会。拟议的研究将利用大量 扩展多个人群的遗传数据，以发现在酒精相关疾病中发挥作用的遗传风险变异 特征（饮酒和 AUD）和与酒精相关的癌症，研究它们之间的遗传相关性，以及 使用孟德尔随机化 (MR) 研究酒精特征与癌症之间的遗传因果关系。 此外，通过整合有关大规模基因表达、eQTL、mQTL、代谢组学的汇总数据 将 QTL 和蛋白质组 QTL 转化为 2 步 MR，我们的目标是识别表达水平相关的基因 与酒精相关的癌症变异，识别调节和表观遗传标记介导 酒精与癌症之间的关系，并确定涉及的相关途径机制 乙醛和可能的其他代谢物。这项研究将帮助我们更好地了解遗传 酒精特征与酒精相关癌症之间关系的机制 改善疾病预防和治疗策略的潜力。