Identification of Novel Candidate Genes for CVD

CVD 新候选基因的鉴定

• 批准号: 7470231
• 负责人: John Blangero
• 金额: $ 57.85万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470231
• 关键词: Candidate Disease Gene; Cardiovascular Diseases; DNA Resequencing; Data; Data Set; Enrollment; European; Exhibits; Family; Gallbladder; Gene Expression; Genes; Genome; Genomics; Genotype; Heart; High Density Lipoprotein Cholesterol; Human; Individual; Lymphocyte; Metabolic; Mexican Americans; Molecular; Nucleotides; Obesity; Participant; Phenotype; Plasma; Principal Investigator; Probability; Promoter Regions; Quantitative Trait Loci; Regulation; Research; Resources; Risk; Risk Factors; Sampling; Sampling Studies; Standards of Weights and Measures; Testing; Transcript; Triglycerides; Variant; Wisconsin; base; cardiovascular disorder risk; clinical phenotype; genetic linkage analysis; novel; programs; promoter; trait

In this project, we propose to use an integrative genomics approach to identify potentially functional regulatory variants in novel candidate genes for cardiovascular disease (CVD) risk. These objectively chosen candidate genes were obtained using large-scale transcriptional profiling of lymphocyte samples from 1,240 San Antonio Family Heart Study (SAFHS) participants. Target candidate loci were nominated based on the existence of significant correlations of quantitative gene expression levels with two major CVD risk factors, HDL-C levels and plasma triglyceride levels. Using our unique family-based resource of quantitative genome-wide transcriptional profiles, we will examine 50 novel candidate genes that exhibit both strong evidence for c/s-regulation of expression levels and significant correlations between expression levels and HDL-C or plasma triglyceride levels. Our prior linkage-based evidence for c/s-acting sequence variation can be exploited as a probabilistic causal anchor to maximize our chance for finding functional variation within proximal promoters. For each of these objectively chosen genes, we will (1) resequence approximately two kilobases of putative promoter region in 182 founder individuals to identify promoter variants; (2) genotype all detected promoter variation in the 1,240 SAFHS samples for which we have transcriptional profiles; (3) test whether promoter sequence variants are associated with gene expression levels of the appropriate candidate gene; (4) test for associations between promoter sequence variants and CVD-related phenotypes; (5) confirm observed associations in two independent samples, and (6) perform molecular functional analysis of the most likely regulatory variants The proposed integrative genomics research paradigm to be used in this project should increase the pace of discovery of the constituent genes of human quantitative trait loci (QTLs) influencing major risk factors for CVD risk. By focusing on genes whose transcripts show evidence for both c/s-regulatory variation and a strong relationship with the focal clinical phenotypes, we should maximize our probability for finding causal players in the CVD risk cascade.

在这个项目中，我们建议使用一种综合基因组学方法来识别潜在的功能 心血管疾病(CVD)风险的新候选基因的调控变异。这些客观选择 通过对1240份淋巴细胞样本进行大规模转录图谱分析，获得了候选基因 圣安东尼奥家庭心脏研究(SAFHS)参与者。目标候选基因座的提名是基于 定量基因表达水平与两个主要心血管疾病危险因素存在显著相关性， 高密度脂蛋白胆固醇水平和血浆甘油三酯水平。 使用我们独特的基于家族的定量全基因组转录图谱资源，我们将 检查50个新的候选基因，这些基因都显示出c/S-表达水平调控的强有力证据 表达水平与高密度脂蛋白胆固醇或血浆甘油三酯水平显著相关。我们的前辈 C/S作用序列变异的连锁证据可以作为概率因果锚来利用 最大限度地增加我们在近端启动子中发现功能变异的机会。对于这些客观上的每一个 选定的基因，我们将(1)对182中大约两千碱基的推定启动子区域进行重新排序 方正个体识别启动子变异；(2)在1240个基因型中全部检测到启动子变异 我们有转录图谱的SAFHS样本；(3)检测启动子序列变体是否 与适当候选基因的基因表达水平相关联；(4)检验 启动子序列变异和CVD相关表型；(5)证实了观察到的两个 独立样本，以及(6)对最可能的调控变异体进行分子功能分析 本项目中将使用的拟议综合基因组学研究范式应增加 影响重大风险的人类数量性状基因座(QTL)组成基因的发现速度 心血管疾病风险的影响因素。通过关注那些转录产物显示c/S调控变异的证据的基因 与局灶性临床表型有很强的相关性，我们应该最大限度地发现 心血管疾病风险级联中的因果参与者。