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: 10490259
• 负责人: Hang Zhou
• 金额: $ 14.99万
• 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/10490259
• 关键词: Acetaldehyde; Acetates; Aerodigestive Tract; African; Alcohol consumption; Alcohol dehydrogenase; Alcoholic Beverages; Alcohols; American; Beverages; Biological; Biological Process; Body mass index; Cause of Death; Colon Carcinoma; Colorectal Cancer; DNA Methylation; Data; Development; East Asian; 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.

项目摘要/摘要 酒精摄入量和饮酒障碍癌症风险的遗传因果关系 饮酒和饮酒障碍（AUD）是全球死亡和残疾的主要原因之一。 乙醇，即饮料酒精，主要被酒精脱氢酶（几种ADH基因）氧化为 乙醛，然后通过醛脱氢酶（主要是Aldh2）排毒为乙酸。乙醛 国际研究机构的研究机构 癌症。累积流行病学证据表明，饮酒与 癌症的发展，包括上层机水，乳腺癌，肝癌和大肠癌；全部5.5％ 癌症归因于酒精，每年总共770,000例。更好地理解分子 酒精增加癌症风险的基础可能导致改善治疗和预防策略。 全基因组关联研究（GWASS）已经确定了与酒精相关性状和癌症的风险基因， 一些基因对两者都显示出多效的影响。但是，酒精与 癌症仍然在很大程度上不清楚。最近，与酒精相关的性状和 癌症提供了回答上述问题的机会。拟议的研究将利用大量 在多个人群中缩放遗传数据，以发现在两种与酒精有关的遗传风险变异 特征（酒精使用和AUD）以及与酒精相关的癌症，研究它们之间的遗传相关性，以及 使用孟德尔随机化（MR）研究酒精性状和癌症之间的遗传因果关系。 另外，通过整合有关大规模基因表达的摘要数据，EQTL，MQTL，代谢组学 QTL和蛋白质组学QTL成2步MR，我们旨在鉴定其表达水平相关的基因 随着酒精相关的癌症变异，确定介导的调节和表观遗传标记 酒精与癌症之间的关系，并确定涉及的相关途径机制 乙醛和其他代谢产物。这项研究将帮助我们更好地了解遗传 酒精性状与酒精相关癌症之间关系的机制与 改善疾病预防和治疗策略的潜力。

项目成果

Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program.

• DOI: 10.1038/s41398-023-02409-2
• 发表时间: 2023-05-05
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Cheng, Youshu;Dao, Cecilia;Zhou, Hang;Li, Boyang;Kember, Rachel L.;Toikumo, Sylvanus;Zhao, Hongyu;Gelernter, Joel;Kranzler, Henry R.;Justice, Amy C.;Xu, Ke
• 通讯作者: Xu, Ke