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: 8472519
• 负责人: Lawrence Joseph Abraham
• 金额: $ 48.31万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472519
• 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.

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。