Untargeted Adductomics to Characterize Ethnic Differences in the Exposome of Smokers

摘要 大约11-24%的吸烟者在一生中会患上肺癌， 非裔美国人和夏威夷原住民吸烟者与白人，日裔美国人， 拉丁裔。即使在调整吸烟量后，这些差异仍然存在。香烟烟雾是一种复杂的 一种化学物质的混合物，包括至少70种已知的致癌物、前致癌物和炎症因子。 属于不同种族的吸烟者可能对香烟烟雾有不同的反应， 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，运动，酒精 消费和环境暴露。这些因素会导致不同数量的DNA和蛋白质 加合物在吸烟者，介导他们的敏感性吸烟诱导的突变和癌症。近期发展 在分析方法和生物信息学中， 使用无针对性或多方面的分析，从外部和内部来源（危险因素）暴露 血红蛋白加合物。血红蛋白是人体血液中含量最丰富的蛋白质，具有相对较长的半衰期， 血红蛋白加合物反映了亲电试剂的累积暴露。内收管切开术方法是 类似于其他组学方法，如基因组学、转录组学和代谢组学， 使人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。 吸烟者的内收神经切断术研究将捕捉个体对吸烟的生理反应， 发现导致肺癌风险的新因素。 我们假设，由于饮食、生活方式和环境方面的遗传差异和种族差异， 暴露，不同种族/人种的人群形成不同数量的蛋白质和DNA加合物， 这导致了接触烟草烟雾后肺癌风险的种族差异。客观 本申请的目的是表征吸烟者、前吸烟者和从不吸烟者的吸烟组， 非洲人血红蛋白加合物形成个体间和种族间差异研究 来自多种族队列（MEC）的美国人、夏威夷原住民、白色人、日裔美国人和拉丁裔吸烟者， 并确定该基因组在改变肺癌风险中的作用。我们的方法是创新的，因为 我们将首次使用血红蛋白来描述外部和内部暴露的总体特征 内收管切除术在一个大的多种族吸烟者群体。 预期结果：我们的研究将有助于深入了解种族差异的起源， 吸烟介导的肺癌，并帮助确定特定的风险因素，发挥最大的作用，在修改 肺癌的风险。对这些风险因素的进一步了解可能会导致预防策略， 有助于克服肺癌风险中的种族/种族差异，并改善人类健康。

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.