Genetic Epidemiology of Lung Cancer

对家族聚集性和暴露后风险差异的研究表明，遗传学在肺癌易感性中发挥作用。两项研究，包括这一项，发现了与肺癌中罕见常染色体基因孟德尔共显性遗传一致的证据，一项连锁研究正在进行中。肺癌的关联研究受到发病年龄晚和疾病快速致命性的限制。在针对I相和II相酶多态性以及DNA修复酶多态性的候选易感基因的研究中报告了不一致的结果。总的来说，这些研究有几个局限性，包括只关注少数多态性，小样本量，由于人群分层和人群间的差异造成的偏倚。发现复杂疾病基因的另一种方法是通过混合作图。最近混合人群，如非洲裔美国人，提供了这种类型的分析最强大的力量。为了进一步描述肺癌的遗传风险，拟议的研究将使用新的方法和最近验证的SNP小组，在仅病例研究设计中确定非裔美国人肺癌的遗传标记。本研究的具体目标是：1）收集800例非裔美国人肺癌病例进行混合定位; 2）在800例病例和200例对照中，使用混合作图方法确定显示与肺癌易感性相关的证据的区域（用于检查模型假设）使用3，011个SNP，已知非洲人和欧洲美国人之间的频率差异> 0.5，并且在整个基因组中间隔1.2cM;及（三）继续扩大有三名或以上肺癌患者的家庭，以作日后的连锁研究。这将是第一个使用混合作图来识别肺癌易感基因的研究。通过关注非洲裔美国人人口，证明混合，这种方法可以成功地使用，是本研究的下一个合乎逻辑的步骤。

Studies of familial aggregation and differences in risk after exposure suggest that genetics plays a role in lung cancer susceptibility. Two studies, including this one, have found evidence consistent with Mendelian codominant inheritance of a rare autosomal gene in lung cancer and one linkage study is underway. Linkage studies in lung cancer are limited by the late age of onset and the rapidly fatal nature of the disease. Inconsistent findings have been reported in studies of candidate susceptibility genes focused on phase I and phase II enzyme polymorphisms and DNA repair enzyme polymorphisms. Overall, these studies have several limitations including a focus on only a small number of polymorphisms, small sample sizes, bias due to population stratification, and variations across populations. An alternative approach to the discovery of genes for complex diseases is through admixture mapping. Recently admixed populations, such as African Americans, provide the most power for this type of analysis. To further characterize genetic risk of lung cancer, the proposed study will use new methodology and a recently validated panel of SNPs in a case-only study design to identify genetic markers for lung cancer in African Americans. The specific aims of the proposed study are: 1) to accrue 800 African American lung cancer cases for admixture mapping; 2) to identify regions showing evidence of linkage to lung cancer susceptibility using admixture mapping methods in 800 cases and 200 controls (used to check model assumptions) using 3,011 SNPs known to differ in frequency by > 0.5 between Africans and European Americans and spaced 1.2cM across the genome; and 3) to continue to extend families with three or more lung cancer affected family members for future linkage studies. This will be the first study to use admixture mapping to identify susceptibility genes for lung cancer. By focusing on the African American population, with demonstrated admixture, this approach can be used successfully and is the next logical step in this research.