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的发展中发挥关键作用。可溶性细胞内粘附分子 (ICAM)-1 与老年人的临床冠心病相关，主要是在病例对照设计中。动物研究中已经提出了合理的途径。我们对年轻人冠状动脉风险发展 (CARDIA) 研究的辅助研究 (R01 HL 53560) 的初步数据表明，CARDIA 15 岁时（平均年龄 40 岁）的 ICAM-1 浓度可预测 5 年后发生的冠状动脉钙化。此外，来自西雅图SNPs NHLBI基因组应用计划的完整DNA序列变异数据已经确定了定量CAM测量和相关表型与CARDIA中的几种血管炎症和细胞粘附候选基因的关联。由于白细胞、内皮细胞和血小板上的大量 CAM 协同工作，协调对血管内皮损伤的炎症反应，并且对动脉粥样硬化早期阶段 CAM 的研究很少，因此我们现在建议测量 7 个额外的 CAM 相关生物标志物存储在 CARDIA 第 7 和 15 年收集的样本，并将这些数据与 CAM 上的 CARDIA 基因型和相关基因相结合，以评估生物标志物、影响它们的遗传位点以及冠状动脉钙化。数据分析将表征 CAM 模式的预测能力，并将使用最先进的单基因座和多基因座遗传分析方法，包括评估基因-基因和基因-环境相互作用。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将通过动脉粥样硬化多种族研究 (MESA) 中的复制进行研究。此外，相关 SNP 的功能评估将通过计算机和体外分析进行，以增强我们研究结果的生物学解释性。我们的研究结果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，并鼓励针对细胞粘附分子的进一步治疗。公共卫生相关性：心血管疾病仍然是美国和西方人群发病和死亡的主要原因。虽然已经确定了几个主要危险因素并作为预防计划的基础，但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。该项目的目标是了解循环粘附分子、其遗传变异与动脉粥样硬化发展之间的关系。该研究的一个主要方面是确定年轻人中的这些关系。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，从而显着降低心血管疾病的发病率。