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

基本信息

项目摘要

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。

项目成果

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Lawrence Joseph Abraham其他文献

Lawrence Joseph Abraham的其他文献

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{{ truncateString('Lawrence Joseph Abraham', 18)}}的其他基金

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
  • 财政年份:
    2010
  • 资助金额:
    $ 48.31万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 48.31万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 48.31万
  • 项目类别:

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