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.
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