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

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 酒精使用和酒精使用障碍（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（几种ADH基因）氧化， 乙醛，然后通过乙醛脱氢酶（主要是ALDH 2）将其解毒为乙酸。乙醛 和酒精饮料被列为致癌物质，对人类的国际研究机构， 癌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，乳腺癌，肝癌和结肠直肠癌; 5.5%的所有 酒精导致的癌症每年高达七十七万例。更好地理解分子 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善。 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， 有些基因对两者都有多效性。然而，酒精和 癌症在很大程度上仍不清楚。最近，对酒精相关性状进行了大型GWAS， 癌症，提供了回答上述问题的机会。拟议的研究将利用大 在多个人群中扩展遗传数据，以发现遗传风险变异在酒精相关的 特征（酒精使用和AUD）和酒精相关癌症，研究它们之间的遗传相关性， 使用孟德尔随机化（MR）研究酒精特征和癌症之间的遗传因果关系。 此外，通过整合关于大规模基因表达、eQTL、mQTL、代谢组学的总结数据， QTL和蛋白质组学QTL的两步MR，我们的目标是确定基因的表达水平相关 与酒精相关的癌症变异，确定调节和表观遗传标记，介导 酒精和癌症之间的关系，并确定相关的途径机制， 乙醛和潜在的其他代谢物。这项研究将有助于我们更好地了解遗传 酒精特征和酒精相关癌症之间关系的基础机制， 改善疾病预防和治疗战略的潜力。

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.