Untargeted Adductomics to Characterize Ethnic Differences in the Exposome of Smokers

摘要 大约11%-24%的吸烟者会在一生中患上肺癌，其中 非裔美国人和夏威夷原住民吸烟者与白人、日裔美国人和 拉丁裔。即使在根据吸烟量进行调整后，这些差异仍然存在。香烟烟雾是一种情结 化学混合物，包括至少70种已知的致癌物质、致癌物质和发炎物质。 不同种族的吸烟者对吸烟的反应可能会因以下原因而有所不同 固有的遗传和表观遗传差异以及与种族相关的生活方式因素，如饮食、锻炼、饮酒 消费和环境暴露。这些因素会导致不同数量的DNA和蛋白质 吸烟者体内的加合物，调节他们对吸烟诱导的突变和癌症的敏感性。最近的发展 在分析方法论和生物信息学中已经使描述人类的整体成为可能 使用无针对性或多方面的分析，从外部和内部来源(曝光组)进行曝光 一种血红蛋白加合物。血红蛋白是人类血液中含量最丰富的蛋白质，半衰期相对较长， 而血红蛋白加合物反映了对亲电体的累积暴露。吸引学的方法是 类似于其他组学方法，如基因组学、转录组学和代谢组学，这些方法是 使我们能够从全球的角度来理解和看待复杂的人类疾病，如癌症。 吸烟者的吸烟学研究将捕捉个体对吸烟的生理反应，可能 发现导致肺癌风险的新因素。 我们推测，由于遗传差异和饮食、生活方式和环境的种族差异 暴露，不同种族/种族的人群形成不同数量的蛋白质和DNA加合物， 这导致暴露在烟草烟雾中的肺癌风险存在种族差异。目标是 这个应用程序的特点是描述吸烟者、曾经吸烟者和从不吸烟者的暴露，以 调查非洲人个体间和种族间/种族间血红蛋白加合物形成的差异 来自多种族队列(MEC)的美国人、夏威夷原住民、白人、日裔美国人和拉丁裔吸烟者， 并确定暴露组在降低肺癌风险中的作用。我们的方法是创新的，因为 我们将首次使用血红蛋白来表征外部和内部暴露的总体 一个庞大的多民族吸烟者群体中的内收切除症。 预期结果：我们的研究将有助于洞察种族差异在敏感性方面的起源 吸烟介导的肺癌，并帮助确定在修饰过程中起最大作用的特定危险因素 肺癌风险。对此类风险因素的更多了解可能会导致预防性战略，从而 帮助克服肺癌风险方面的民族/种族差异，改善人类健康。

ABSTRACT About 11-24% of smokers will develop lung tumors over their lifetime, with a greater cancer incidence in African American and Native Hawaiian cigarette smokers as compared with Whites, Japanese Americans, and Latinos. These differences persist even after adjusting for smoking amounts. Cigarette smoke is a complex mixture of chemicals including at least 70 known carcinogens, procarcinogens, and inflammatory agents. Smokers belonging to different ethnic groups may have variable responses towards cigarette smoke due to inherent genetic and epigenetic differences and ethnicity-related lifestyle factors such as diet, exercise, alcohol consumption, and environmental exposures. These factors can lead to differing amounts of DNA and protein adducts in smokers, mediating their sensitivity to smoking-induced mutations and cancer. Recent development in analytical methodologies and bioinformatics have made it possible to characterize the totality of human exposures from both external and internal sources (the exposome) using untargeted or multifaceted analyses of hemoglobin adducts. Hemoglobin is the most abundant protein in human blood with a relatively long half-life, and hemoglobin adducts reflect cumulative exposures to electrophiles. The adductomics approach is analogous to other -omics methodologies such as genomics, transcriptomics, and metabolomics, which are making it possible to understand and view complex human diseases such as cancer from a global perspective. Adductomics studies in smokers will capture individual physiological responses to smoking, potentially uncovering new factors that contribute to lung cancer risk. We hypothesize that due to genetic differences and ethnic variations in diet, lifestyle, and environmental exposures, human populations of different ethnicity/race form variable numbers of protein and DNA adducts, which contributes to ethnic disparities in lung cancer risk following exposure to tobacco smoke. The objective of this application is to characterize the exposomes of smokers, former smokers, and never smokers, to investigate inter-individual and inter-ethnic/racial differences in formation of hemoglobin adducts in African American, Native Hawaiian, White, Japanese American, and Latino smokers from the Multiethic Cohort (MEC), and to establish the role of the exposome in modifying lung cancer risk. Our approach is innovative because we will, for the first time, characterize the totality of external and internal exposures using hemoglobin adductomics in a large multiethnic group of smokers. Expected outcomes: Our studies will help provide insight into the origins of ethnic variability in sensitivity to smoking-mediated lung cancer and help identify specific risk factors that play the greatest role in modifying lung cancer risk. An increased understanding of such risk factors may lead to preventative strategies that will help overcome ethnic/racial disparities in lung cancer risk and improve human health.