Ethnic/Racial Differences in DNA Repair

肺癌是美国和世界范围内癌症死亡的主要原因，其中大部分是 吸烟引起的癌症。多种族队列(MEC)研究有力地表明， 在与吸烟相关的肺癌风险方面，美国民族/种族群体之间存在重大差异。我们会 研究非裔美国人更易受非裔美国人 与烟草相关的化学物质比欧美人的DNA修复能力降低所致。这 将通过测定非洲人或非裔美国人的淋巴细胞的敏感性进行评估 欧裔美国人对三种烟草致癌物质的活性形式的毒性和致突变活性， 4(甲基亚硝基)-L-(S吡啶)-1丁酮，苯并[a]芘和1，S-丁二烯。我们将测试我们的 通过执行以下特定目的来进行假设：1.确定敏感度是否存在差异 欧洲裔美国人和非洲人对活性烟草烟雾致癌物的细胞毒性效应的研究 利用国际HapMap EB病毒(EBV)转化的来源于 欧洲裔美国人(CEU)和约鲁班(非洲，YRI)人口的三人组；2.确定是否有 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 利用HapMap B淋巴细胞系研究烟草烟雾致癌物质；3.确定两者是否有差异 欧美人和美国人之间烟草烟雾衍生致癌物DNA加合物的修复率 使用HapMap淋巴细胞系的非洲人或从欧美和非洲分离的淋巴细胞 项目5中的非裔美国吸烟者；4.进行候选基因和全基因组关联研究 在AIMS 1-3中测量的毒物学表型，以确定是否特定的基因类型驱动观察到的 与项目1合作的表型。总的来说，这些研究将揭示是否存在人种/种族 烟草致癌物引起的DNA损伤修复的差异以及这些修复差异是否转化为 对这些化学物质的遗传毒性影响的敏感性的差异。

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.