Integrative Genomics of Vanin Gene Expression in Relation to CVD Risk

Vanin 基因表达与 CVD 风险相关的综合基因组学

• 批准号: 8073579
• 负责人: Lawrence Joseph Abraham
• 金额: $ 49.27万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073579
• 关键词: 6q22; Adopted; Alleles; Antioxidants; Biological; Cardiovascular Diseases; Cell Culture Techniques; Cell Line; Cholesterol; Chromosomes; Cysteamine; DNA; Data; Data Set; EMSA; Elements; Family; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome; Genomics; Genotype; HDL-triglyceride; Habits; Health; Heart; High Density Lipoproteins; Human; Hydrogen Peroxide; Hydrolysis; Hypertriglyceridemia; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Introns; Knowledge; Lead; Life Style; Linker-Scanning Mutagenesis; Lipid Peroxidation; Lipids; Lymphocyte; Mediating; Mediation; Messenger RNA; Methods; Mexican Americans; Modeling; Mus; Oxidative Stress; Pantetheine; Papio; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population Study; Process; Prostaglandins; Proteins; Regulation; Regulatory Element; Reporter Genes; Risk; Risk Factors; Rotenone; SNP genotyping; Small Interfering RNA; Study Section; Testing; Therapeutic; Therapeutic Intervention; Thick; Transcript; Transcriptional Regulation; Triglycerides; Up-Regulation; Variant; Vitamins; base; cardiovascular disorder risk; cobaltous chloride; combinatorial; cytokine; deletion analysis; genetic linkage analysis; genome wide association study; genome-wide; high risk; in vitro Model; insight; knock-down; mRNA Expression; novel; pantetheinase; pantothenate; prevent; promoter; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): Classical family-based genetic studies have convincingly demonstrated that genes have a large effect on the risk of cardiovascular disease (CVD); their identification however is proving elusive. We have recently combined quantitative genome-wide mRNA expression phenotypes with linkage analysis in our SAFHS study population to identify the Vanin-1 gene on chromosome 6q22 as a novel CVD risk factor. Vanin-1 is a pantetheinase that catalyzes the hydrolysis of D-pantetheine generating pantothenate (vitamin B5) and cysteamine, a potent anti-oxidant known to prevent lipid peroxidation. We have shown that the expression of Vanin-1 is cis-regulated and correlates positively with HDL-C levels in both humans and baboons and negatively with triglyceride (TG) levels in humans. In mice, reduced vanin-1 levels also are associated with a more CVD - prone phenotype of increased TG levels, as seen in humans. These results suggest that the Vanin-1 gene may be potentially involved in lipid mediation. In this project we propose to use an integrative genomics approach to comprehensively determine how the Vanin-1 gene is transcriptionally regulated and to identify other (perhaps novel) genes that participate with Vanin-1 in the global regulatory networks that confer risk of CVD. Specifically, we will: 1) identify the functional SNPs that influence Vanin-1 gene expression starting with our statistically prioritized isocorrelated redundant variant sets; 2) identify the remaining non- variant DNA regulatory elements and associated transcription factors that control basal and inducible Vanin-1 gene expression; 3) identify and validate upstream regulators of Vanin-1 expression levels using genome-wide association analysis and in vitro knockdown experiments; 4) identify downstream genes in the Vanin-1 regulatory networks by association with functional Vanin-1 regulatory variants, and validate by in vitro knockdown; and 5) validate any novel upstream or downstream genes identified in Aims 2 - 4 using SNP- based association analyses with CVD-related risk phenotypes such as HDL-C, TG, and carotid-wall thickness. Any novel insight into biological mechanisms that predispose individuals to CVD holds the promise of potential new therapies and a significant reduction of this considerable health burden. PUBLIC HEALTH RELEVANCE: Despite the current availability of therapies involving lipid-lowering drugs the incidence of cardiovascular disease (CVD) remains very high, indicating that there is a need for additional therapeutic strategies. Many lines of evidence suggest that aside from adopting healthy lifestyle habits, patients with established CVD, and those at high risk, may benefit from drugs that increase circulating levels of HDL-C (the good cholesterol). We have recently identified a gene that appears to be involved in the regulation of lipid levels, and in particular HDL-C levels. In this project we aim to understand how this gene is regulated and the mechanisms by which it exerts lipid-modifying effects. The knowledge gained may lead to better methods for identifying those at greatest risk of CVD and point to new strategies for drug therapy.

描述（由申请人提供）：基于家庭的基于家庭的遗传研究令人信服地证明，基因对心血管疾病的风险（CVD）具有很大的影响；然而，他们的识别证明是难以捉摸的。我们最近在SAFHS研究人群中将定量基因组的mRNA表达表型与连锁分析相结合，以鉴定6q22染色体上的Vanin-1基因是一种新型的CVD风险因素。 VANIN-1是一种胆汁蛋白酶，可催化D-pantetheine产生的泛酸盐（维生素B5）和cysteamine的水解，这是一种有效的抗氧化剂，已知可预防脂质过氧化。我们已经表明，VANIN-1的表达是顺式调节的，并且与人类和狒狒的HDL-C水平呈正相关，并且与人类的甘油三酸酯（TG）水平负相关。在小鼠中，降低的Vanin -1水平也与人类所见的更为CVD - 更容易增加TG水平的表型有关。这些结果表明，Vanin-1基因可能与脂质介导有关。在这个项目中，我们建议使用一种综合基因组学方法来全面确定Vanin-1基因在转录调节中的调节方式，并识别其他（也许是新颖的）基因在全球监管网络中参与CVD风险的全球监管网络中。具体而言，我们将：1）确定从我们统计优先相关的冗余变体集开始的影响Vanin-1基因表达的功能SNP； 2）确定控制基础和可诱导的Vanin-1基因表达的剩余非变异DNA调节元件以及相关的转录因子； 3）使用全基因组关联分析和体外敲低实验来识别和验证VANIN-1表达水平的上游调节剂； 4）通过与功能性Vanin-1调节变体相关的Vanin-1调节网络中的下游基因，并通过体外敲低验证； 5）使用基于SNP的关联分析与CVD相关的风险表型，例如HDL-C，TG和Harotid-Wall厚度，验证在目标2-4中鉴定出的任何新型上游或下游基因。任何对生物学机制的新颖洞察力，使个人对CVD产生易感性，并具有潜在的新疗法的希望，并大大减轻了这种大量健康负担。 公共卫生相关性：尽管目前有涉及降低脂质药物的疗法可用性，但心血管疾病（CVD）的发生率仍然很高，表明需要其他治疗策略。许多证据表明，除了养成健康的生活方式习惯，既定CVD和高风险的患者外，还可能受益于增加HDL-C（良好胆固醇）循环水平的药物。我们最近确定了似乎参与脂质水平的调节，尤其是HDL-C水平的基因。在这个项目中，我们旨在了解如何调节该基因以及其发挥脂质修饰作用的机制。获得的知识可能会导致更好的方法来识别CVD风险最大的人，并指出药物治疗的新策略。