Genetic Epidemiology of Lung Cancer

对家庭聚集性和暴露后风险差异的研究表明，遗传因素在肺癌易感性中发挥了作用。包括这一项在内的两项研究已经发现了与肺癌中一种罕见常染色体基因的孟德尔共显性遗传一致的证据，其中一项连锁研究正在进行中。肺癌的关联研究受到发病年龄较晚和疾病的迅速致命性的限制。关于候选易感基因的研究，主要集中在I、II相酶多态和DNA修复酶多态，但报道的结果并不一致。总体而言，这些研究有几个局限性，包括只关注少量的多态性，样本量小，由于人口分层而产生的偏见，以及不同人口之间的差异。发现复杂疾病基因的另一种方法是通过混合作图。最近混杂的人群，如非裔美国人，为这种类型的分析提供了最大的动力。为了进一步确定肺癌的遗传风险，拟议的研究将使用新的方法和最近验证的SNPs小组，在仅限病例的研究设计中确定非裔美国人肺癌的遗传标记。这项拟议研究的具体目标是：1)收集800例非裔美国人肺癌病例，用于混合图谱；2)使用混合图谱方法，在800例病例和200名对照(用于检验模型假设)中，使用3,011个SNP，这些SNP在非洲人和欧洲裔美国人之间的频率不同，并且基因组间距1.2 cM；以及3)继续扩大有三个或更多受肺癌影响的家庭成员的家庭，以进行未来的联系研究。这将是第一次使用混合图谱来识别肺癌易感基因的研究。通过把重点放在非裔美国人群体上，并证明他们是混血儿，这种方法可以成功地使用，也是这项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.