Confirmation of SNPs Associated with Aggressive PCa in a GWA Study

描述（由申请人提供）：标题：GWA研究中与侵袭性前列腺癌相关的snp的确认前列腺癌（PCa）的遗传易感性已经得到证实，并且是所有常见癌症中最强的。许多基因的遗传序列变异，每个基因都有中等风险，被认为是遗传易感性的共同基础。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，该研究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100万例病例和对照。到目前为止，我们已经完成了该GWA的第一阶段，研究了来自瑞典人群（CAPS）的500例侵袭性病例和500例对照的550K个snp，其中包括20K个非同义snp。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，以大幅增加GWA的样本量，并在独立研究人群中系统地随访大量snp。我们提出了四个具体的目标来验证基因组中遗传序列变异可能增加或改变PCa风险的假设。目标1)作为第二阶段，我们将在另外800例侵袭性PCa病例和800例瑞典对照中对500K snp和50K补充snp进行基因型分析。将对第一阶段和第二阶段的受试者进行联合关联分析，以选择snp进行进一步确认。目标2)作为第三阶段，我们将在约翰霍普金斯医院另外2000例侵袭性PCa病例和1000例对照中检测约6500个snp与PCa的关联。将在所有可用的受试者中对这些snp进行联合分析，以确定达到全基因组显著性水平的snp。目标3)对全基因组显著snp周围的基因组区域进行精细的图谱分析，以确定在所有3300例侵袭性PCa病例和2300例对照中与PCa风险最密切相关的变异。目的4)通过瑞典全国性局部PCa随访研究（FU-study）和来自约翰霍普金斯医院的500对进展者和非进展者的广泛随访信息，评估5000例PCa风险变异与疾病进展的关系。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。

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.