Association of a common variant of the PPAP2B gene with cardiovascular disease.

PPAP2B 基因的常见变异与心血管疾病的关联。

• 批准号: 8774196
• 负责人: ANDREW J MORRIS
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774196
• 关键词: Accounting; Address; Admission activity; Affect; Alleles; Atherosclerosis; Attention; Binding Sites; Biological Availability; Biological Markers; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cell Surface Receptors; Cell surface; Cells; Cholesterol; Clinical; Congestive Heart Failure; Coronary Arteriosclerosis; Coronary artery; Data Analyses; Defect; Deposition; Development; Diabetes Mellitus; Diagnosis; Disease; Disease susceptibility; Employee Strikes; Enzymes; Event; Experimental Models; Family; Frequencies; Gene Expression; Genes; Genetic Polymorphism; Genetic Variation; Genetic screening method; Genotype; Goals; Health; Healthcare; Hospitals; Human; Human Genetics; Hypertension; Individual; Integral Membrane Protein; Investigation; Knowledge; LDL Cholesterol Lipoproteins; Lead; Leukocytes; Lipids; Lysophospholipids; Mediator of activation protein; Membrane; Messenger RNA; Minor; Mus; Mutation; Myocardial Infarction; Myocardial Ischemia; Nuclear; Pathology; Plasma; Positioning Attribute; Predisposition; Prevention; Process; Protein Dephosphorylation; Proteins; RNA Splicing; RNA Stability; Reagent; Recording of previous events; Research; Research Project Grants; Resolution; Ribonucleoproteins; Risk; Risk Factors; Role; Sampling; Series; Single Nucleotide Polymorphism; Smooth Muscle; Smooth Muscle Myocytes; Specific qualifier value; Testing; Therapeutic; Tissues; Transcript; Translating; United States; Untranslated RNA; Validation; Variant; Vascular Endothelial Cell; Vascular Smooth Muscle; Veterans; Work; base; cardiovascular disorder risk; cardiovascular risk factor; disorder risk; enzyme activity; enzyme substrate; genetic variant; genome wide association study; improved; innovation; inorganic phosphate; lipid metabolism; lipid phosphate phosphatase; lysophosphatidic acid; mortality; novel strategies; novel therapeutics; protective effect; receptor; research study; tool; vascular inflammation

DESCRIPTION (provided by applicant): Ischemic heart disease, caused by atherosclerosis of the coronary arteries, remains the most frequent cause of mortality among Veterans despite extensive investigation into its pathobiology, the identification of many risk factors, and development of new therapeutic strategies. The hallmark features of endothelial damage, lipid deposition, smooth muscle cell proliferation and vascular inflammation contribute to the development and complications of atherosclerosis. The bioactive lysophospholipids, sphingosphine-1-phosphate (S1P) and lysophosphatidic acid (LPA), act on cell surface receptors expressed by many vascular cells. These lipids are positioned to serve as mediators of the cellular events contributing to atherosclerosis, and their role is supported by emerging evidence from experimental models. The lipid phosphate phosphatase 3 (encoded by the PPAP2B gene) is a cell surface integral membrane protein that regulates the bioavailability of S1P and LPA by catalyzing their dephosphorylation to generate lipid products that are not receptor active. Analysis of data from a series of genome-wide association studies (GWAS) focuses attention on a striking association between a single nucleotide polymorphism (SNP) in the PPAP2B locus and coronary artery disease. This rs17114036 SNP lies in an intronic, non-coding region of the gene that could affect gene expression. How genetic variation in PPAP2B confers risk of coronary artery disease is unknown, in large part because of a lack of understanding of LPP3 function in vascular cells. In this application, we present evidence that vascular cell LPP3 serves as an intrinsic negative regulator of vascular inflammation, suppresses smooth muscle cell proliferation, and promotes endothelial barrier function. These protective effects of LPP3 suggest that PPAP2B polymorphisms associated with reduced gene expression could aggravate cellular events underlying atherosclerosis and increase the likelihood of myocardial infarction. The broad long-term goal of this research project is to explain how human genetic variation at the PPAP2B locus alters the risk of myocardial infarction and apply that knowledge to improve the diagnosis and therapy of ischemic heart disease. We have assembled a team of experts whose knowledge spans all aspects of the proposed research to position ourselves to validate the function of the PPAP2B locus in atherosclerosis. In this proposal, we will test our central hypothesis, which is that the minor allele of rs17114036 in PPAP2B reduces gene expression and that lower levels of LPP3 promote atherosclerosis. We will apply unique tools that we have developed to study LPP3 and our considerable expertise to test our central hypothesis. Firstly, we will identify the mechanism by which in the rs17114036 SNP in PPAP2B affects LPP3 expression and activity. We predict that rs17114036 affects a U1 splisome binding site and thereby reduces gene expression. We will test this working hypothesis by determining if the minor allele of rs17114036 associates with altered LPP3 transcript and protein levels in white blood cells and arterial tissue and by examining the consequences, of the polymorphism on RNA splicing and stability. Secondly, we will establish a mechanistic role for LPP3 in experimental atherosclerosis. Based on our Preliminary Studies of vascular pathology in mice with tissue-specific defects in smooth muscle and endothelial LPP3, the working hypothesis of this section is that LPP3 protects against vascular inflammation and that reduced expression will therefore accelerate atherosclerosis. We will test this working hypothesis by determining the consequences of vascular tissue specific deficiency of LPP3 on the development of atherosclerosis in mice. The experiments proposed in this application are an important step in functionally validating a common genetic variant in PPAP2B as a cardiovascular risk predictor in humans. Establishing PPAP2B, its product LPP3 and the lipid substrates of this enzyme as risk predictors and mediators of CAD promises to identify important and innovative targets for the development of new biomarkers and/or therapeutics.

描述（由申请人提供）： 尽管对病理生物学的广泛研究，许多危险因素的鉴定以及新的治疗策略的发展，但由冠状动脉动脉的动脉粥样硬化引起的缺血性心脏病仍然是退伍军人死亡的最常见原因。内皮损伤，脂质沉积，平滑肌细胞增殖和血管炎症的标志性特征有助于动脉粥样硬化的发育和并发症。生物活性溶血磷脂，链膦1-磷酸（S1P）和溶血磷脂酸（LPA）作用于许多由许多血管细胞表达的细胞表面受体。这些脂质可作为导致动脉粥样硬化的细胞事件的介体，并由实验模型的新兴证据支持它们的作用。脂质磷酸磷酸磷酸酶3（由PPAP2B基因编码）是一种细胞表面积分膜蛋白，通过催化其去磷酸化以产生非受体活性的脂质产物来调节S1P和LPA的生物利用度。分析来自全基因组关联研究（GWAS）的数据的分析将注意力集中在PPAP2B基因座和冠状动脉疾病中的单个核苷酸多态性（SNP）之间的引人注目的关联。该rs17114036 SNP位于基因的内含子，非编码区域，可能影响基因表达。 PPAP2B的遗传变异如何赋予冠状动脉疾病的风险，这在很大程度上是由于缺乏对血管细胞LPP3功能的了解。在此应用中，我们提供了证据表明，血管细胞LPP3是血管炎症的内在阴性调节剂，抑制平滑肌细胞增殖并促进内皮屏障功能。 LPP3的这些保护作用表明，与基因表达降低相关的PPAP2B多态性可能会加剧动脉粥样硬化的基础细胞事件并增加心肌梗塞的可能性。 该研究项目的长期长期目标是解释PPAP2B基因座的人类遗传变异如何改变心肌梗塞的风险，并应用这些知识来改善缺血性心脏病的诊断和治疗。我们组建了一个专家团队，他们的知识跨越了拟议的研究的各个方面，以定位自己，以验证PPAP2B基因座的功能。在此提案中，我们将测试我们的中心假设，即PPAP2B中RS17114036的小等位基因降低了基因表达，而LPP3的较低水平促进了动脉粥样硬化。我们将应用开发的独特工具来研究LPP3和我们的大量专业知识来检验我们的中心假设。首先，我们将确定PPAP2B中RS17114036 SNP中的机制会影响LPP3的表达和活性。我们预测RS17114036会影响U1 Splisome结合位点，从而降低基因表达。 我们将通过确定rs17114036的次要等位基因是否与白细胞和动脉组织中的LPP3转录物和蛋白质水平改变，并检查RNA剪接和稳定性的多态性的后果，并检查其后果，并研究该假设。其次，我们将在实验性动脉粥样硬化中确立LPP3的机械作用。基于我们对平滑肌和内皮LPP3组织特异性缺陷的小鼠血管病理学的初步研究，本节的工作假设是LPP3可以预防血管炎症，因此降低的表达将加速动脉粥样硬化。 我们将通过确定LPP3的血管组织特异性缺乏对小鼠动脉粥样硬化发展的后果来检验这一工作假设。 本应用程序中提出的实验是在功能上验证PPAP2B中常见的遗传变异的重要一步，作为人类的心血管风险预测因子。建立PPAP2B，其产品LPP3和该酶的脂质底物作为CAD的风险预测因子和介体有望确定开发新生物标志物和/或治疗剂的重要和创新目标。