Cellular Adhesion Molecules: Genes, Phenotypes, and Coronary Atherosclerosis

细胞粘附分子：基因、表型和冠状动脉粥样硬化

• 批准号: 7878588
• 负责人: Myron D Gross
• 金额: $ 76.28万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878588
• 关键词: Adhesions; Adult; Age; Alabama; Ancillary Study; Animals; Arterial Fatty Streak; Arts; Atherosclerosis; Biological Markers; Biology; Blood Platelets; Blood Vessels; CCL2 gene; CXCR4 gene; Calcium; Candidate Disease Gene; Cardiovascular Diseases; Cell Adhesion; Cell Adhesion Molecules; Chemotactic Factors; Clinical; Collaborations; Complex; Computer Simulation; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; DNA Sequence; Data; Data Analyses; Development; Disease; E-Selectin; Elderly; Endothelial Cells; Fractalkine; Funding; Future; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Haplotypes; Immunoglobulins; In Vitro; Incidence; Individual; Individual Differences; Inflammation; Inflammatory; Inflammatory Response; Inherited; Injury; Integrins; Leukocytes; Life; Measurement; Measures; Methods; Minnesota; Molecular; Morbidity - disease rate; National Heart, Lung, and Blood Institute; North Carolina; P-Selectin; Participant; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Plasma; Play; Population; Prevention; Prevention program; Public Health; Recurrence; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Selectins; Staging; Statistical Methods; Time; United States; Universities; Variant; Vascular Cell Adhesion Molecule-1; Washington; Work; base; cardiovascular disorder risk; case control; chemokine; chemokine receptor; cohort; coronary artery calcification; design; emerging adult; gene environment interaction; gene function; genetic analysis; insight; lifestyle intervention; middle age; mortality; new therapeutic target; novel; population based; programs; public health relevance; therapeutic target; vascular inflammation; young adult

DESCRIPTION (provided by applicant): Cellular adhesion molecules (CAMs) may play a key role in atherosclerotic development. Soluble intracellular adhesion molecule (ICAM)-1 relates to clinical coronary heart disease in older people, mostly in case-control designs. Plausible pathways have been suggested in animal studies. Preliminary data from our ancillary study (R01 HL 53560) to the Coronary Artery Risk Development in Young Adults (CARDIA) study show that ICAM-1 concentrations at CARDIA year 15 (average age 40) predict incident coronary calcification 5 years later. Furthermore, complete DNA sequence variation data from the SeattleSNPs NHLBI Program for Genomic Application have identified associations of quantitative CAM measurement and related phenotypes to several vascular inflammation and cellular adhesion candidate genes in CARDIA. Because numerous CAMs on leukocytes, endothelial cells, and platelets work in concert to coordinate the inflammatory response to vascular endothelial injury and there has been little study of CAMs in the early stages of atherosclerosis, we now propose to measure 7 additional CAM-related biomarkers in stored samples collected at CARDIA years 7 and 15, and to combine these data with CARDIA genotypes on CAM and related genes to assess the relationships among the biomarkers, genetic loci influencing them, and coronary artery calcification. Data analyses will characterize the predictive power of patterns of CAMs and will use state-of-the art single-locus and multi-locus genetic analysis methods, including assessment of gene-gene and gene-environment interaction. Validity of genetic main effects and interactions on plasma CAM concentrations and risk of coronary calcification will be studied by replication in the MultiEthnic Study of Atherosclerosis (MESA). In addition, functional assessment of associated SNPs will be performed through in silico and in vitro analyses to enhance biologic interpretability of our findings. Our findings are likely to provide new insights into the biologic basis of the early stages of atherosclerosis and encourage further therapies directed toward cell adhesion molecules. PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains a major cause of morbidity and mortality in the United States and Western populations. While several major risk factors have been identified and are the basis for prevention programs, a further understanding of the cellular and molecular basis of cardiovascular disease will aid in the prevention and treatment of this disease. The objective of this project is gaining an understanding of the relationships between circulating adhesion molecules, their genetic variation and the development of atherosclerosis. A primary aspect of the study is the identification of these relationships in young adults. The results of this study may help identify methods of early prevention and new therapeutic targets, which could significantly reduce the incidence of cardiovascular disease.

描述（由申请人提供）：细胞粘附分子（CAM）可能在动脉粥样硬化发展中起关键作用。可溶性细胞内粘附分子（ICAM）-1与老年人临床冠心病有关，主要是病例对照设计。动物研究中提出了合理的途径。我们对年轻成人冠状动脉风险发展（CARDIA）研究的辅助研究（R 01 HL 53560）的初步数据显示，CARDIA 15年（平均年龄40岁）时的ICAM-1浓度可预测5年后的冠状动脉钙化事件。此外，来自SeattleSNPs NHLBI基因组应用程序的完整DNA序列变异数据已经确定了定量CAM测量和相关表型与CARDIA中几个血管炎症和细胞粘附候选基因的相关性。由于白细胞、内皮细胞和血小板上的许多CAM协同工作以协调对血管内皮损伤的炎症反应，并且在动脉粥样硬化的早期阶段很少有CAM的研究，我们现在建议在CARDIA第7年和第15年收集的储存样品中测量7个额外的CAM相关生物标志物，并将这些数据与CARDIA基因型和CAM相关基因结合联合收割机，以评估生物标志物、影响它们的遗传位点和冠状动脉钙化之间的关系。数据分析将表征CAM模式的预测能力，并将使用最先进的单位点和多位点遗传分析方法，包括评估基因-基因和基因-环境相互作用。将通过多种族动脉粥样硬化研究（梅萨）的重复研究，研究遗传主要效应和相互作用对血浆CAM浓度和冠状动脉钙化风险的有效性。此外，将通过计算机模拟和体外分析对相关SNP进行功能评估，以增强我们发现的生物学可解释性。我们的发现可能为动脉粥样硬化早期阶段的生物学基础提供新的见解，并鼓励进一步针对细胞粘附分子的治疗。公共卫生相关性：心血管疾病仍然是美国和西方人群发病率和死亡率的主要原因。虽然已经确定了几个主要的风险因素，并为预防计划的基础，进一步了解心血管疾病的细胞和分子基础将有助于预防和治疗这种疾病。本项目的目的是了解循环粘附分子及其遗传变异与动脉粥样硬化发展之间的关系。这项研究的一个主要方面是在年轻人中识别这些关系。这项研究的结果可能有助于确定早期预防方法和新的治疗靶点，这可能会显着降低心血管疾病的发病率。