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

基本信息

批准号：
7756692
负责人：
Jianfeng Xu
金额：
$ 60.05万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/7756692
关键词：
Affect Cancer Patient Candidate Disease Gene Case-Control Studies Characteristics Data Diagnosis Disease Disease Association Disease Progression Disease susceptibility Etiology Follow-Up Studies Frequencies Funding Genes Genetic Genetic Markers 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 public health relevance success

项目摘要

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.

描述（由申请人提供）：标题：在 GWA 研究中确认与侵袭性 PCa 相关的 SNP 前列腺癌 (PCa) 的遗传易感性已得到充分证实，并且是所有常见癌症中最强的。许多基因中的遗传序列变异（每个变异都具有中等风险）被认为共同构成了遗传易感性。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特征明确的研究人群，总计超过 10,000 个病例和对照。到目前为止，我们通过研究来自瑞典人群 (CAPS) 的 500 个侵袭性病例和 500 个对照中的 550K SNP，包括 20K 非同义 SNP，完成了拟议 GWA 的第一阶段。为了进一步提高识别中度风险 SNP 的能力，我们提出了一项研究，以显着增加 GWA 的样本量，并系统地跟踪独立研究人群中的大量 SNP。我们提出了四个具体目标来检验基因组中遗传序列变异可能增加或改变前列腺癌风险的假设。目标 1) 作为第二阶段，我们将在来自瑞典的另外 800 例侵袭性 PCa 病例和 800 例对照中对 500K SNP 和 50K 补充 SNP 子集进行基因分型。将在第一阶段和第二阶段的受试者之间进行联合关联分析，以选择 SNP 进行进一步确认。目标 2) 作为第三阶段，我们将在来自约翰·霍普金斯医院的另外 2,000 个侵袭性 PCa 病例和 1,000 个对照中测试约 6,500 个 SNP 的 PCa 关联。将对所有可用受试者中的这些 SNP 进行组合分析，以确定达到全基因组显着性水平的 SNP。目标 3) 对全基因组重要 SNP 周围的基因组区域进行精细作图分析，以识别所有 3,300 例侵袭性 PCa 病例和 2,300 例对照中与 PCa 风险最密切相关的变异。目标 4) 评估 5,000 例 PCa 风险变异与疾病进展的关联，其中包括瑞典全国局部 PCa 随访研究（FU 研究）和 500 配对的进展者和非进展者的广泛随访信息来自约翰·霍普金斯医院。 PCa 风险变异的识别可能会影响对该疾病的理解、预防、诊断和治疗。