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

项目摘要/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)是全世界导致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(几个ADH基因)氧化成 乙醛，然后由乙醛脱氢酶(主要是ALDH2)解毒为乙酸酯。乙醛 酒精饮料被国际研究机构归类为对人类致癌 癌症。累积的流行病学证据表明，饮酒与 发生癌症，包括上呼吸道、乳腺癌、肝癌和结直肠癌；占所有癌症的5.5% 癌症可归因于酒精，每年总计77万例。更好地理解分子 酒精增加癌症风险的基础可能会导致改善治疗和预防策略。 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， 一些基因对这两种基因都表现出多效性。然而，酒精和酒精之间的遗传关系 癌症在很大程度上仍不清楚。最近，对与酒精相关的性状和 巨蟹座提供了回答上述问题的机会。拟议的研究将利用大型 扩大多个人群中的遗传数据以发现在酒精相关的两种疾病中发挥作用的遗传风险变量 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、代谢组的汇总数据 QTL和蛋白质组QTL转化为两步法MR，我们的目的是识别其表达水平相关的基因 对于与酒精相关的癌症变异，确定调节和表观遗传标记介导 酒精与癌症的关系，并确定相关的途径机制，涉及 乙醛，可能还有其他代谢物。这项研究将有助于我们更好地了解 酒精特征和酒精相关癌症之间关系的基础机制，与 改进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.