Confirmation of SNPs Associated with Aggressive PCa in a GWA Study

GWA 研究中确认与侵袭性 PCa 相关的 SNP

• 批准号: 7603059
• 负责人: Jianfeng Xu
• 金额: $ 60.38万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-04 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603059
• 关键词: Affect; Cancer Patient; Candidate Disease Gene; Case-Control Studies; Characteristics; Classification; Data; Diagnosis; Disease; Disease Association; Disease Progression; Disease susceptibility; Etiology; Follow-Up Studies; Frequencies; Funding; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Grant; Hospitals; Inherited; Joints; Lead; Linkage Disequilibrium; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Methods; Nature; Oncogenes; Pathway interactions; Phenotype; Population; Population Study; Prevention; Probability; Request for Applications; Research Design; Research Personnel; Risk; Role; Sample Size; Single Nucleotide Polymorphism; Staging; Stratification; Structure of base of prostate; Study Subject; Sweden; Testing; Time; Universities; Variant; Work; cancer genome; cancer risk; case control; clinically relevant; design; disorder risk; experience; follow-up; forest; genetic association; genome wide association study; genome-wide; genotyping technology; improved; men; novel; novel strategies; population based; success

DESCRIPTION (provided by applicant): Title: Confirmation of SNPs Associated with Aggressive PCa in a GWA study A genetic predisposition to prostate cancer (PCa) is well established and is the strongest among all common cancers. Inherited sequence variants in a number of genes, each conferring a moderate risk, are believed to collectively underlie the genetic predisposition. To systematically identify these risk variants, we have initiated an ambitious genome-wide association (GWA) study that includes several large and well characterized study populations in Sweden and Johns Hopkins Hospital, totaling > 10,000 cases and controls. Thus far, we have completed the 1st stage of this proposed GWA by studying 550K SNPs, including 20K nonsynonymous SNPs, among 500 aggressive cases and 500 controls from a Swedish population (CAPS). To further improve the power of identifying moderate risk SNPs, we propose a study to considerably increase the sample size for a GWA and systematically follow-up a large number of SNPs among independent study populations. We propose four specific aims to test the hypothesis that inherited sequence variants in the genome may increase or modify PCa risk. Aim 1) As the 2nd stage, we will genotype 500K SNPs and a subset of 50K supplement SNPs among an additional 800 aggressive PCa cases and 800 controls from Sweden. A joint association analysis among subjects in stages 1 & 2 will be performed to select SNPs for further confirmation. Aim 2) As the 3rd stage, we will test for PCa associations for the ~6,500 SNPs among an additional 2,000 aggressive PCa cases and 1,000 controls from Johns Hopkins Hospital. A combined analysis will be performed for these SNPs among all available subjects to identify SNPs that reach genome-wide significance level. Aim 3) Perform a fine mapping analysis at genomic regions surrounding the genome-wide significant SNPs to identify variants that are most strongly associated with PCa risk among all 3,300 aggressive PCa cases and 2,300 controls. Aim 4) Assess association of the PCa risk variants with the disease progression among 5,000 cases with extensive follow-up information from a Swedish Nationwide Follow-Up study of Localized PCa (FU-study) and 500 matched-pairs of progressors and non-progressors from Johns Hopkins Hospital. The identification of PCa risk variants may impact the understanding, prevention, diagnosis, and treatment of this disease. PUBLIC HEALTH RELEVANCE: We propose to identify inherited sequence variants in the genome that confer moderate risk to prostate cancer (PCa) using a genome-wide association (GWA) study among more than 10,000 subjects from multiple study populations. The identified genes may advance our understanding on the etiology of PCa and could be used to better predict the risk for developing PCa. The focus on aggressive PCa is particularly important because this is the most clinically relevant form of PCa.

描述（由申请人提供）：标题：在GWA研究中，与侵略性PCA相关的SNP的确认是对前列腺癌（PCA）的遗传易感性（PCA）的确认，并且是所有常见癌症中最强的。据信，许多基因中的遗传序列变体都被认为是遗传倾向的基础。为了系统地识别这些风险变异，我们启动了一项雄心勃勃的全基因组关联（GWA）研究，其中包括瑞典和约翰·霍普金斯医院的几个大型且表征良好的研究人群，总计> 10,000例病例和对照。到目前为止，我们已经通过研究550k SNP（包括20k非单义词SNP）完成了该拟议GWA的第一阶段，其中包括500例侵略性案例和500个来自瑞典人口（CAPS）的控制。为了进一步提高识别中等风险SNP的能力，我们提出了一项研究，以大大增加GWA的样本量，并系统地跟踪独立研究人群中大量SNP。我们提出了四个特定的目的，以检验基因组中遗传序列变体可能会增加或改变PCA风险的假设。 AIM 1）作为第二阶段，我们将在另外800个侵略性PCA病例和800个对照中的基因型500K SNP和50K补充SNP的子集。将在第1阶段和第2阶段进行联合关联分析以选择SNP以进行进一步确认。目标2）作为第三阶段，我们将在另外2,000个激进的PCA病例和约翰·霍普金斯医院的1,000例控制中测试约6,500个SNP的PCA协会。在所有可用受试者中，将对这些SNP进行联合分析，以识别达到全基因组显着性水平的SNP。 AIM 3）对围绕全基因组显着SNP的基因组区域进行精细的映射分析，以识别所有3,300例侵略性PCA病例和2,300个对照中与PCA风险最密切相关的变体。 AIM 4）评估PCA风险变体与5,000例疾病进展的关联，并在瑞典全国范围内进行了广泛的后续信息，来自瑞典的全国PCA（FU-Study）（FU-Study）和500名匹配的经验者和非培训者的匹配对手。 PCA风险变异的鉴定可能会影响对该疾病的理解，预防，诊断和治疗。公共卫生相关性：我们建议在基因组中识别遗传序列变体，这些变异使用来自多个研究人群的10,000多名受试者中的全基因组关联（GWA）研究赋予前列腺癌（PCA）中等风险。确定的基因可能会提高我们对PCA病因的理解，并可以用来更好地预测开发PCA的风险。对积极PCA的关注尤其重要，因为这是PCA最相关的形式。