Genetic Susceptibility for Lung Cancer in African Americans

描述（由申请人提供）：肺癌是非洲裔美国人癌症死亡的主要原因，该人群的风险比白种人高约1/3。最近，我们和其他人进行的合作研究已经确定了高加索人染色体15q25, 5p15和6p21上的区域与肺癌风险高度显著相关。染色体15q和6p上的关联区域位于白种人基因组中显示出非常强烈的连锁不平衡水平的区域，因此确定特定的致病基因和致病变异是有问题的。在非洲裔美国人中，我们对染色体15q25区域的初步研究显示出更多的连锁不平衡的点状模式，因此对非洲裔美国人的研究将提供更精确的遗传变异定位。初步数据表明多种遗传因素的作用，但我们的初步研究使用有限数量的样本和snp进行，尚不足以准确确定因果变异的位置。我们的初步数据显示，非裔美国人5p和15q染色体snp对风险的影响比白种人更大。因此，我们建议对来自三个中心的样本进行基因分型，其中包括1300多例肺癌病例和1300例对照，在三个感兴趣的区域中每个区域的400个SNP位点。我们还将对祖先信息标记进行基因分型，以便我们可以评估祖先背景作为混杂因素。第一个目标是在三个基因组区域进行密集的SNP分析，以亚定位和表征三个基因组区域对肺癌风险的影响。第二个目标将进行更详细的建模，以估计吸烟、性别和遗传因素对肺癌风险的共同影响。这项分析将使我们能够确定非裔美国人患肺癌的风险特别高的群体。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death among African-Americans and this population has approximately 1/3 higher risk than Caucasians. Recently, collaborative studies that we and others have lead have identified regions on chromosomes 15q25, 5p15 and 6p21 that are highly significantly associated with lung cancer risk in Caucasians. The regions of association on chromosome 15q and 6p lie in areas of the genome that show very strong levels of linkage disequilibrium in Caucasians so that identifying the specific causal gene and causal variant(s) is problematic. In African- Americans, our preliminary study of the region on chromosome 15q25 shows a much more punctate pattern of linkage disequilbrium so that studies of the African-American population will provide a more precise localization of genetic variants. The preliminary data suggest the role of multiple genetic factors, but our initial studies conducted with a limited number of samples and SNPs are not yet sufficient to identify precisely the location(s) of causal variants. Our preliminary data show stronger effects on risks from SNPs on chromosomes 5p and 15q in African-Americans than in Caucasians. We therefore propose to genotype samples from three centers comprising over 1300 lung cancer cases and 1300 controls for 400 SNP loci in each of the three regions of interest. We will also genotype ancestry informative markers so that we can evaluate the ancestral background as a confounder. The first aim will perform dense SNP analysis in three genomic regions to sublocalize and characterize the impact on lung cancer risk in three genomic regions. The second aim will perform more detailed modeling to estimate joint effects of smoking, sex and genetic factors on lung cancer risk. This analysis will allow us to identify groups of African-American individuals at particularly higher risks for developing lung cancer.