Genome-wide Case-control Association Study of Pancreatic Cancer in Jews

描述(由申请人提供)：流行病学研究一直发现，与非犹太白人相比，犹太人患胰腺癌的风险更高。BRCA1/2突变或其他已知风险因素不能解释这种额外的风险。因此，我们建议在犹太受试者中检查在胰腺癌队列和病例对照联盟(PanScan)全基因组关联研究(GWAS)中观察到的最显著的单核苷酸多态(SNP)关联，以进行探索性GWAS以确定更多与犹太人群中的胰腺癌相关的SNP，并评估犹太血统与胰腺癌之间关系的遗传基础。为了做到这一点，我们将使用来自PanScan和约翰霍普金斯大学题为“胰腺癌易感基因的验证和精细绘图”研究的Gwas数据。在我们的研究中，犹太受试者被确定为一组与自我报告的犹太血统密切相关的遗传标记。根据PanScan和约翰·霍普金斯大学研究的参与者进行的初步样本量计算，估计约有500个犹太病例和300个未受影响的犹太控制措施。我们将使用程序Eenersoft(v.3.0)进行主成分分析，该分析将从基因上识别其他种族/民族群体中的犹太主体。我们将通过使用耶鲁大学、约翰·霍普金斯大学和纪念斯隆·凯特林研究中自我报告的犹太受试者的子集来验证这些基因识别的犹太人，这些研究都是泛扫描和约翰·霍普金斯大学研究中的子研究。我们将执行SNP复制分析，进行GWAS，并将使用程序PLINK(v.1，07)：全基因组关联分析工具集评估遗传贡献。每个SNP将使用Logistic回归模型，结果变量为胰腺癌，每个SNP为预测变量。对于候选基因方法，任何与P值小于0.05的关联都将被认为是显著的，而对于GWAS方法，与P值的关联小于10-6。这将是第一个确定与BRCA1/2突变不同的遗传基础的研究，这是犹太人患胰腺癌风险过高的原因。这项工作的结果将为确定基因相互作用开辟道路，并将开始探讨在犹太人口中进行胰腺癌基因筛查的可能性。

DESCRIPTION (provided by applicant): Epidemiologic studies have consistently found Jews to be at increased risk of pancreatic cancer compared to non-Jewish whites. This excess risk is not accounted for by BRCA1/2 mutations or by other known risk factors. We therefore propose to examine in Jewish subjects the most significant single nucleotide polymorphism (SNP) associations observed in the Pancreatic Cancer Cohort and Case-Control Consortium (PanScan) genome-wide association study (GWAS), to perform an exploratory GWAS to identify additional SNPs associated with pancreatic cancer in the Jewish population, and to assess genetic underpinning of the relationship between Jewish ancestry and pancreatic cancer. To do this, we will use GWAS data from PanScan and from the Johns Hopkins University study titled "Validation and Fine-Scale Mapping of Pancreatic Cancer Susceptibility Loci." In our study, Jewish subjects with be identified with a panel of genetic markers that correlate strongly with self-reported Jewish ancestry. Preliminary sample size calculations, based upon participants in the PanScan and Johns Hopkins University studies, give an estimate of around 500 Jewish cases and 300 unaffected Jewish controls. We will use the program Eigensoft (v.3.0) to conduct a principal component analysis that will genetically identify Jewish subjects among other racial/ethnic groups. We will validate these genetically identified Jews by using a subset of self-reported Jewish subjects in the Yale University, Johns Hopkins, and Memorial Sloan Kettering studies, all sub-studies in the PanScan and Johns Hopkins University studies. We will perform the SNP replication analysis, conduct the GWAS, and will assess genetic contribution using the program PLINK (v.1, 07): whole genome association analysis toolset. Logistic regression models will be used for each SNP, with pancreatic cancer as the outcome variable and each SNP as a predictor variable. Any association with P-value less than 0.05 will be considered significant for the candidate gene approach, and less than 10-6 for the GWAS approach. This will be the first study to determine a genetic basis, distinct from BRCA1/2 mutations, for the excess risk of pancreatic cancer in Jews. Results from this work will open paths to identify genetic interactions and will begin to approach the possibility of genetic screening for pancreatic cancer in the Jewish population.