Ethnic/Racial Differences in DNA Repair

肺癌是美国和世界范围内癌症死亡率的主要原因，其中大多数人都患有肺癌。 吸烟引起的癌症。多种族队列（MEC）研究强烈表明， 美国不同种族/民族在与吸烟相关的肺癌风险方面存在重大差异。我们将 调查假设，即非洲裔美国人更容易受到致癌特性， 烟草相关的化学物质比欧洲裔美国人的DNA修复能力降低的结果。这 将通过确定来自非洲人或非裔美国人的淋巴细胞的敏感性来评估， 欧洲裔美国人对三种烟草致癌物的活性形式的毒性和致突变活性， 4-（甲基亚硝胺基）-1-（S-吡啶基）-1-丁酮、苯并[a]芘和1，S-丁二烯。我们将测试我们的 假设通过执行以下具体目标：1。确定是否存在灵敏度差异 欧洲裔美国人和非洲人之间对激活的烟草烟雾致癌物的细胞毒性作用的关系 使用国际人类基因组单体型图Epstein-Barr病毒（EBV）转化的B淋巴细胞系， 欧洲裔美国人（CEU）和约鲁邦人（非洲人，YRI）的三人组; 2.确定是否存在 欧洲裔美国人和非洲人对激活的基因毒性效应的敏感性差异 烟草烟雾致癌物使用HapMap B淋巴细胞系; 3.确定是否存在差异 在欧洲裔美国人和美国人之间烟草烟雾衍生的致癌物DNA加合物的修复率中， 非洲人使用HapMap淋巴细胞系或从欧洲美洲人和非洲人分离的淋巴细胞， 项目5中的非洲裔美国人吸烟者; 4。进行候选基因和全基因组关联研究， 目的1-3中测定的毒理学表型，以确定特定基因型是否驱动观察到的 表型与项目1合作。总的来说，这些研究将揭示是否存在种族/种族 烟草致癌物引起的DNA损伤修复的差异，如果这些修复差异 对这些化学物质的遗传毒性效应的敏感性差异。

Lung cancer is the leading cause of cancer mortality in the U.S. and woridwide with the majority of these cancers caused by smoking. The Multiethnic Cohort (MEC) study strongly demonstrated that there are major differences among US ethnic/racial groups in lung cancer risk associated with smoking. We will investigate the hypothesis that African Americans are more susceptible to the carcinogenic properties of tobacco-associated chemicals than European Americans as a result of reduced DNA repair capacity. This will be assessed by determining the sensitivity of lymphocytes from Africans or African Americans and European Americans to the toxic and mutagenic activity of activated forms ofthe three tobacco carcinogens, 4 (methylnitrosamino)-l-(S pyridyl)-1 butanone, benzo[a]pyrene and 1,S-butadiene. We will test our hypothesis by performing the following specific aims: 1. Determine if there is a difference in sensitivity between European Americans and Africans to the cytotoxic effects of activated tobacco smoke carcinogens using the International HapMap Epstein-Barr virus (EBV)-transformed B-lymphocyte cell lines derived from trios of European Americans (CEU) and Yoruban (African, YRI) populations; 2. Determine if there is a difference in sensitivity between European Americans and Africans to the genotoxic effects of activated tobacco smoke carcinogens using the HapMap B-lymphocyte cell lines; 3. Determine if there is a difference in repair rates for tobacco smoke-derived carcinogen DNA adducts between European Americans and Africans using the HapMap lymphocyte cell lines or lymphocytes isolated from European American and African American smokers in Project 5; 4. Perform candidate gene and genome-wide association studies of the toxicological phenotypes measured in Aims 1-3 to determine if specific genotypes drive the observed phenotypes in collaboration with Project 1. Collectively, these studies will reveal if there are ethnic/racial differences in repair of tobacco carcinogen derived DNA damage and if these differences in repair translate into differences in sensitivity to the genotoxic effects of these chemicals.