Genetic Susceptibility for Lung Cancer in African Americans

描述(申请人提供)：肺癌是非裔美国人癌症死亡的主要原因，这一人群的风险比高加索人高约三分之一。最近，我们和其他人牵头的合作研究已经确定了染色体15q25、5p15和6p21上与高加索人肺癌风险高度相关的区域。染色体15q和6p上的关联区位于基因组的区域，在高加索人中显示出非常强的连锁不平衡水平，因此识别特定的因果基因和因果变体(S)是有问题的。在非裔美国人中，我们对染色体15q25上的区域的初步研究显示了更具点状的连锁不平衡模式，因此对非裔美国人群体的研究将提供更精确的遗传变异定位。初步数据表明多个遗传因素的作用，但我们对有限数量的样本和SNPs进行的初步研究还不足以准确确定因果变异的位置(S)。我们的初步数据显示，在非裔美国人中，染色体5p和15q上的SNPs对风险的影响比高加索人更强。因此，我们建议对来自三个中心的样本进行基因分型，这些样本包括1300多例肺癌病例和1300名对照，分别针对三个感兴趣区域的400个SNP基因座。我们还将对祖先信息标记进行基因分型，这样我们就可以将祖先背景作为混杂因素进行评估。第一个目标将在三个基因组区域进行密集的SNP分析，以细分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联合影响。这一分析将使我们能够识别出患肺癌风险特别高的非裔美国人群体。

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.