Genetic determinants of gene expression phenotypes in aggressive prostate cancer

描述(由申请人提供)： 这种调节变异被认为在形成个体之间的表型差异方面发挥了重要作用，因此也很可能影响疾病的易感性和进展。在这项研究中，我们建议利用表达QTL定位和共表达基因网络分析来识别和表征与前列腺癌侵袭性表型有关的候选基因和遗传变异。我们的假设是，大多数导致前列腺癌侵袭性表型的基因变异对候选基因的表达具有调节作用，并且只有通过检查原始组织(这里是前列腺癌)才能完全了解调节性SNPs。为了验证这一假设，我们将使用病例-病例研究设计，并应用一种创新但可行的方法，将DNA序列变异和基因表达与临床特征信息相结合。这四个具体目标是：1.利用基于表达遗传学的eQTL作图方法寻找新的侵袭性相关候选SNPs；2，利用基于整合系统遗传学的网络分析方法寻找新的侵袭性相关候选SNPs；3.对于AIMS 1和2中发现的新候选SNP，进行额外的基于关联的研究，以确认它们与前列腺癌侵袭性相关表型的关联；以及4.通过精细作图识别候选因果SNP，认识到目标3中确定的候选eSNP很可能与因果SNP处于连锁不平衡状态。了解侵袭性表型背后的遗传机制将对预防策略、预后和潜在的靶向治疗产生重大影响。

DESCRIPTION (provided by applicant): The regulatory variation is believed to play an important role in shaping phenotypic differences among individuals and thus is also very likely to influence disease susceptibility and progression. In this study, we propose to take advantage of the expression QTL mapping and co-expressed gene network analysis to identify and characterize candidate genes and genetic variants that are responsible for aggressive phenotype of prostate cancer. Our hypothesis is that most genetic variants responsible for an aggressive phenotype of prostate cancer have regulatory effect on candidate gene expression and complete understanding of regulatory SNPs can only be achieved by examining primary tissue (here, prostate). To test this hypothesis, we will use a case-case study design and apply an innovative yet feasible approach by integrating DNA sequence variation and gene expression with clinical trait information. The four Specific Aims are: 1. Identify novel aggressiveness-related candidate SNPs by utilizing an expression genetics-based eQTL mapping approach; 2, Identify novel aggressiveness-related candidate SNPs by utilizing an integrative systems genetics-based network analysis approach; 3. For the novel candidate SNPs identified in Aims 1 and 2, perform additional association-based studies to confirm their association with an aggressiveness-related phenotype for prostate cancer; and 4. Identify candidate causal-SNPs by fine mapping, recognizing that the candidate eSNPs identified in Aim 3 will most likely be in linkage disequilibrium with the causal-SNPs. Understanding genetic mechanisms underlying the aggressive phenotype will have significant impact on prevention strategies, prognosis and potentially targeted therapy.