A Genome-wide Association Study of Prostate Cancer in African Americans

描述(申请人提供)：前列腺癌是男性发病率和死亡率的主要原因之一。目前，我们不了解潜在的病因，也不知道为什么不同的群体，如非裔美国人，患病率更高。前列腺癌的风险因素仍然难以捉摸，除了年龄、有前列腺癌家族病史或非洲血统外，直到最近，没有任何遗传或非遗传(即生活方式)风险因素一直被证明有助于人口中疾病风险的变化。在这项申请中，我们建议开展一项大规模的合作努力，以揭示非裔美国人男性前列腺癌的基因预测因素。为了这一努力，我们组建了一个多机构的研究团队，他们在少数族裔人群中具有前列腺癌研究的经验，他们渴望并愿意从他们已有的研究中汇集资源、标本和数据，并为一个共同的目标密切合作。为了确定导致非裔美国男性前列腺癌风险的遗传因素，我们建议进行一项强大的、多阶段的全基因组关联研究。在第一阶段，我们将在1500名非裔美国人前列腺癌患者和1500名对照中对100万个单核苷酸多态(SNPs)进行基因分型。在第二阶段，我们将对24,000个SNPs进行后续基因分型，这些SNP在另外1,626个非裔美国人病例和1,867个对照中显示出显著的主效应和与前列腺癌已知风险变量(例如8q24)的相互作用。在第三阶段，我们将进一步检查从第一阶段+第二阶段开始的1,124例非洲裔美国人病例和1,163名对照病例的基因关联。在这项研究中，我们还将通过对3900例前列腺癌病例和4350名西非、日本、拉丁裔和欧洲裔美国血统的对照进行复制测试，来评估非裔美国人扫描中发现的变异对泛种族的影响。在这个数据集中，我们还将检查相关变量、环境因素(从而更好地定义这些因素的作用)和疾病严重性之间的相互作用。我们期望这项工作将大大提高人们对前列腺癌病因和前列腺癌风险的种族/民族差异的认识，并指导未来预防、早期发现、预后甚至治疗措施的发展。公共卫生相关性：该项目的目标是确定非裔美国男性前列腺癌的常见风险等位基因。为了这一努力，我们组建了一个多机构的研究团队，他们在少数族裔人群中具有前列腺癌研究的经验，他们渴望并愿意从他们已有的研究中汇集资源、标本和数据，并为一个共同的目标密切合作。更具体地说，我们建议对前列腺癌进行一项多阶段的全基因组关联研究，其中将包括4250名非洲裔美国人病例和4530名非洲裔美国人男性对照。我们将研究相关变异在其他种族/民族人群中的泛种族影响，并将环境和生活方式风险因素纳入关联测试，以帮助更好地确定非洲裔美国人人口中最有可能患这种常见癌症的亚群。我们期望这项工作的发现将指导未来预防、早期发现和预后策略的发展。

DESCRIPTION (provided by applicant): Prostate cancer is one of the leading causes of morbidity and mortality among men. At the moment, we do not understand the underlying etiology, or why different groups, such as African Americans, have higher rates of disease. Risk factors for prostate cancer have remained elusive and aside from age, having a family history of the disease or African ancestry, until recently, no genetic or non-genetic (i.e., lifestyle) risk factors have been consistently demonstrated to contribute to variation in disease risk in the population. In this application, we propose to undertake a large-scale collaborative effort to uncover genetic predictors of prostate cancer in African American men. For this effort, we have assembled a multi-institutional team of investigators with experience in prostate cancer research in minority populations who are eager and willing to pool resources, specimens and data from their established studies, and to work closely together towards a common goal. To identify genetic factors that contribute to prostate cancer risk in African American men we propose to conduct a well-powered multi-stage genome-wide association study. In stage 1 we will genotype 1,000,000 single nucleotide polymorphisms (SNPs) in 1,500 African American prostate cancer cases and 1,500 controls. In stage 2 we will perform follow-up genotyping of 24,000 SNPs that demonstrate significant main effects and interactions with known risk variants for prostate cancer (e.g. 8q24) in an additional 1,626 African American cases and 1,867 controls. In stage 3, we will further examine genetic associations from stage 1+2 in an additional 1,124 African American cases and 1,163 controls. In this study we will also assess the pan-ethnic effects of the variants identify in the African American scan, by replication testing in 3,900 prostate cancer cases and 4,350 controls of West African, Japanese, Latino and European American ancestry. In this dataset, we will also examine interactions between associated variants, environmental factors (thereby better defining the role of these factors) and disease severity. We expect this work to significantly advance knowledge of the etiology of prostate cancer and racial/ethnic disparities in prostate cancer risk, and to guide the development of future preventive, early detection, prognostic and even therapeutic measures. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify common risk alleles for prostate cancer in African American men. For this effort, we have assembled a multi-institutional team of investigators with experience in prostate cancer research in minority populations who are eager and willing to pool resources, specimens and data from their established studies, and to work closely together towards a common goal. More specifically, we propose to conduct a multi-stage genome-wide association study of prostate cancer, which will include 4,250 African American cases and 4,530 African American male controls. We will examine the pan-ethnic effects of associated variants in other racial/ethnic populations as well as incorporate environment and lifestyle risk factors in association testing to assist in better defining the subgroups of the African American population at greatest risk of developing this common cancer. We expect findings from this work to guide the development of future preventive, early detection and prognostic strategies.