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: 7783637
• 负责人: Lawrence Joseph Abraham
• 金额: $ 50.41万
• 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/7783637
• 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; 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; 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）：经典的以家族为基础的遗传学研究已经令人信服地证明，基因对心血管疾病（CVD）的风险有很大的影响;然而，它们的识别被证明是难以捉摸的。我们最近在我们的SAFHS研究人群中将定量全基因组mRNA表达表型与连锁分析相结合，以确定染色体6 q22上的Vanin-1基因是一种新的CVD危险因素。Vanin-1是一种泛酰巯基乙胺酶，其催化D-泛酰巯基乙胺的水解，生成泛酸盐（维生素B5）和半胱胺，半胱胺是一种已知可防止脂质过氧化的有效抗氧化剂。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，与人类的甘油三酯（TG）水平呈负相关。在小鼠中，降低的vanin-1水平也与TG水平升高的更易发生CVD的表型相关，如在人类中所见。这些结果表明Vanin-1基因可能潜在地参与脂质介导。在这个项目中，我们建议使用整合基因组学方法来全面确定Vanin-1基因是如何转录调控的，并确定其他（可能是新的）基因，这些基因与Vanin-1一起参与全球调控网络，从而增加CVD的风险。具体而言，我们将：1）鉴定影响Vanin-1基因表达的功能性SNP，从我们的统计上优先的等相关冗余变体集合开始; 2）鉴定控制基础和诱导型Vanin-1基因表达的剩余非变体DNA调控元件和相关转录因子; 3）使用全基因组关联分析和体外敲低实验鉴定和验证Vanin-1表达水平的上游调节因子; 4）通过与功能性Vanin-1调节变体的关联来鉴定Vanin-1调节网络中的下游基因，并通过体外敲低来验证;和5）使用基于SNP的关联分析与CVD相关风险表型如HDL-C、TG和颈动脉壁厚度来验证目的2 - 4中鉴定的任何新的上游或下游基因。任何新的洞察力的生物机制，易患心血管疾病的个人持有的承诺，潜在的新疗法和显着减少这一相当大的健康负担。 公共卫生相关性：尽管目前有涉及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，除了采取健康的生活习惯外，患有心血管疾病的患者和高风险患者可能会从增加HDL-C（好胆固醇）循环水平的药物中获益。我们最近发现了一个基因，似乎参与调节血脂水平，特别是HDL-C水平。在这个项目中，我们的目标是了解这个基因是如何调节的，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最危险的心血管疾病，并指出新的药物治疗策略。