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)：经典的基于家族的遗传学研究令人信服地证明，基因对心血管疾病(CVD)的风险有很大影响；然而，事实证明，它们的识别是难以捉摸的。我们最近在SAFHS研究人群中结合全基因组定量mRNA表达表型和连锁分析，确定染色体6q22上的Vanin-1基因是一个新的CVD危险因素。Vanin-1是一种泛氨酸酶，催化D-泛氨酸的水解生成泛酸(维生素B5)和半胱胺，半胱胺是一种有效的抗氧化剂，可防止脂质过氧化。我们已经证明，Vanin-1的表达是受顺式调节的，并且在人类中与高密度脂蛋白-C水平呈正相关，在人类中与甘油三酯(TG)水平呈负相关。在小鼠中，降低的Vanin-1水平也与更容易发生心血管疾病的甘油三酯水平升高的表型有关，就像在人类中看到的那样。这些结果表明，Vanin-1基因可能参与了脂质调节。在这个项目中，我们建议使用综合基因组学方法来全面确定Vanin-1基因是如何转录调控的，并在全球调控网络中识别与Vanin-1一起参与CVD风险的其他(可能是新的)基因。具体地说，我们将：1)从我们统计上优先的等位基因相关冗余变异体集合开始，识别影响Vanin-1基因表达的功能SNPs；2)识别其余控制基础和可诱导Vanin-1基因表达的非变异DNA调控元件和相关转录因子；3)通过全基因组关联分析和体外基因敲除实验，识别和验证Vanin-1表达水平的上游调控；4)通过与Vanin-1功能调控变异体的关联，识别Vanin-1调控网络中的下游基因，并通过体外基因敲除实验进行验证；以及5)通过基于SNP的关联分析，验证AIMS 2-4中发现的任何新的上游或下游基因与心血管疾病相关风险表型，如高密度脂蛋白胆固醇、甘油三酯和颈动脉壁厚度。对使个人易患心血管疾病的生物学机制的任何新见解都有望找到潜在的新疗法，并显着减轻这一相当大的健康负担。 公共卫生相关性：尽管目前有降脂药物的治疗方法，但心血管疾病(CVD)的发病率仍然很高，这表明需要额外的治疗策略。许多证据表明，除了养成健康的生活习惯外，已确诊的心血管疾病患者和高危患者可能会受益于提高循环中高密度脂蛋白-C(有益胆固醇)水平的药物。我们最近发现了一个似乎与调节血脂水平，特别是高密度脂蛋白胆固醇水平有关的基因。在这个项目中，我们的目标是了解该基因是如何调节的，以及它发挥调脂作用的机制。所获得的知识可能会导致更好的方法来识别那些心血管疾病风险最高的人，并为药物治疗指明新的策略。