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: 8245892
• 负责人: Lawrence Joseph Abraham
• 金额: $ 50.03万
• 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/8245892
• 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）：经典的基于家庭的遗传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，他们的身份证明是难以捉摸的。我们最近在我们的SAFHS研究人群中结合了定量全基因组mRNA表达表型和连锁分析，确定了染色体6q22上的Vanin-1基因是一个新的心血管疾病危险因素。Vanin-1是一种泛酸酶，它催化d -泛酸水解生成泛酸盐（维生素B5）和半胱胺，半胱胺是一种有效的抗氧化剂，已知可防止脂质过氧化。我们已经证明，Vanin-1的表达是顺式调节的，与人类和狒狒的HDL-C水平呈正相关，与人类的甘油三酯（TG）水平负相关。在小鼠中，降低的vanin-1水平也与增加的TG水平的CVD倾向表型相关，正如在人类中所见。这些结果提示Vanin-1基因可能参与脂质介导。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，并识别其他（可能是新的）基因，这些基因与Vanin-1一起参与全球调控网络，从而导致心血管疾病的风险。具体来说，我们将：1)确定影响Vanin-1基因表达的功能snp，从统计上优先的等相关冗余变异集开始；2)鉴定控制基础和诱导型Vanin-1基因表达的剩余非变异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敲低实验，鉴定并验证Vanin-1表达水平的上游调控因子；4)通过与功能性Vanin-1调控变异体的关联，确定Vanin-1调控网络中的下游基因，并通过体外敲除进行验证；5)利用基于SNP的cvd相关风险表型（如HDL-C、TG和颈动脉壁厚度）关联分析，验证Aims 2 - 4中发现的任何新的上游或下游基因。任何关于个体易患心血管疾病的生物学机制的新见解都有望带来潜在的新疗法，并显著减少这一相当大的健康负担。