Prediction and Progression of Carotid Artery Disease

颈动脉疾病的预测和进展

• 批准号: 7652441
• 负责人: Gail Pairitz Jarvik
• 金额: $ 70.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652441
• 关键词: Age; Animals; Antioxidants; Apolipoprotein A-I; Biological; Body mass index; C-reactive protein; Carotid Arteries; Carotid Artery Diseases; Cause of Death; Cholesterol; Collaborations; Coronary Arteriosclerosis; Cotinine; Data Set; Diabetes Mellitus; Disease Progression; Evaluation; Genes; Genetic Determinism; Genetic Variation; Genotype; Haplotypes; Hospitals; Human; Hypertension; Linkage Disequilibrium; Lipoprotein (a); Lipoproteins; Logistic Regressions; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Magnetic Resonance Imaging; Measures; Mediation; Outcome; Pathway interactions; Peroxidases; Pharmaceutical Preparations; Phenotype; Plasma; Predisposition; Principal Investigator; Proteins; Race; Risk Factors; Role; Sampling; Single Nucleotide Polymorphism; Site; Smoke; Stenosis; Stroke; Structure; Variant; Vascular Diseases; Visit; aryldialkylphosphatase; case control; cohort; disorder risk; genetic variant; glutathione peroxidase; longitudinal analysis; multidisciplinary; oxidation; programs; sex

DESCRIPTION (provided by applicant): We propose this renewal of RO1 HL67406 "Prediction and Progression of Carotid Artery Disease" (CAAD). CAAD is an important risk factor for stroke, the third leading cause of death in the U.S., and its risk factors overlap significantly with those of coronary artery disease, the major cause of death. Strong evidence of an important role of lipoprotein and vessel wall oxidation in vascular disease has emerged from both animal and human studies. As outlined in the Progress section, this multidisciplinary project has established that low paraoxonase (PON1) activity is predictive of CAAD, identified additional functional variation in PON1, evaluated the role of PON1 functional genotype and haplotypes effects in CAAD progression and prediction, and examined the linkage disequilibrium structure of PON1 and its effects on outcome prediction. We propose to continue and expand upon these productive studies, expanding our analyses to all common variation in a group of 29 low density lipoprotein and vessel wall oxidation pathway genes using a tagSNP approach as well as to 4 oxidative phenotypes that have been implicated in vascular disease prediction by ourselves or others. These phenotypes are LDL susceptibility to oxidation, PON1 activity, myeloperoxidase protein level, and glutathione peroxidase level, 3 of which at least preliminarily predict case status in our cohort. In addition to examining these factors in cases and controls, we will examine them in a unique 36 month longitudinal carotid magnetic resonance imaging (MR) progression dataset. This will allow us to evaluate whether these oxidative loci and phenotypes impact progression, as well as risk, of disease. Major aims are: Aim 1: Identify common genetic variation in 29 oxidative loci that predict either CAAD case-control status or progression of CAAD measured by magnetic resonance imaging (MR). Aim 2: Investigate the role of oxidative phenotypes myeloperoxidase, glutatione peroxidase, LDL susceptibility to ex vivo oxidation, and PON1 activity in the prediction of CAAD case-control status and progression measured by MR. Aim 3: Pathway evaluation of oxidative loci and phenotypes in prediction of CAAD.

描述（由申请人提供）：我们建议更新RO1 HL67406“颈动脉疾病的预测和进展”（CAAD）。CAAD是卒中的重要危险因素，卒中是美国第三大死亡原因，其危险因素与主要死亡原因冠状动脉疾病的危险因素有显著重叠。在动物和人类研究中都出现了脂蛋白和血管壁氧化在血管疾病中的重要作用的有力证据。如进展部分所述，这个多学科项目已经确定了低对氧磷酶（PON1）活性可以预测CAAD，确定了PON1的其他功能变异，评估了PON1功能基因型和单倍型效应在CAAD进展和预测中的作用，并研究了PON1的连锁不平衡结构及其对预后预测的影响。我们建议继续并扩展这些富有成效的研究，使用标签snp方法将我们的分析扩展到29组低密度脂蛋白和血管壁氧化途径基因的所有常见变异，以及我们自己或他人与血管疾病预测有关的4种氧化表型。这些表型包括LDL对氧化的易感性、PON1活性、髓过氧化物酶蛋白水平和谷胱甘肽过氧化物酶水平，其中3个至少初步预测了我们队列中的病例状态。除了在病例和对照组中检查这些因素外，我们还将在一个独特的36个月颈动脉纵向磁共振成像（MR）进展数据集中检查它们。这将使我们能够评估这些氧化基因座和表型是否影响疾病的进展和风险。主要目标是：目标1：确定29个氧化位点的常见遗传变异，这些基因可以通过磁共振成像（MR）预测CAAD病例对照状态或CAAD的进展。目的2：研究氧化表型髓过氧化物酶、谷氨酸过氧化物酶、LDL对体外氧化的易感性和PON1活性在预测mr测量的CAAD病例对照状态和进展中的作用。目的3：氧化位点和表型在CAAD预测中的途径评估。

项目成果

HDL-3 is a superior predictor of carotid artery disease in a case-control cohort of 1725 participants.

• DOI: 10.1161/jaha.114.000902
• 发表时间: 2014-06-25
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Kim DS;Burt AA;Rosenthal EA;Ranchalis JE;Eintracht JF;Hatsukami TS;Furlong CE;Marcovina S;Albers JJ;Jarvik GP
• 通讯作者: Jarvik GP

Additional Common Polymorphisms in the PON Gene Cluster Predict PON1 Activity but Not Vascular Disease.

• DOI: 10.1155/2012/476316
• 发表时间: 2012
• 期刊: Journal of lipids
• 影响因子: 5.3
• 作者: Kim DS;Burt AA;Ranchalis JE;Richter RJ;Marshall JK;Eintracht JF;Rosenthal EA;Furlong CE;Jarvik GP
• 通讯作者: Jarvik GP

Predictors of surface disruption with MR imaging in asymptomatic carotid artery stenosis.

• DOI: 10.3174/ajnr.a1842
• 发表时间: 2010-03
• 期刊: AJNR. American journal of neuroradiology
• 作者: Underhill HR;Yuan C;Yarnykh VL;Chu B;Oikawa M;Dong L;Polissar NL;Garden GA;Cramer SC;Hatsukami TS
• 通讯作者: Hatsukami TS