Cellular Adhesion Molecules: Genes, Phenotypes, and Coronary Atherosclerosis

描述(由申请人提供)：细胞黏附分子(CAM)可能在动脉粥样硬化的发展中起关键作用。可溶性细胞间黏附分子(ICAM)-1与老年人的临床冠心病有关，主要是病例对照设计。在动物研究中，已经提出了合理的途径。我们的青年冠状动脉风险发展(CARDIA)辅助研究(R01 HL 53560)的初步数据显示，ICAM-1浓度在CARDIA第15年(平均年龄40岁)预测5年后发生的冠状动脉钙化。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中的几个血管炎症和细胞黏附候选基因的关联。由于白细胞、内皮细胞和血小板上的大量CAM协同工作以协调血管内皮细胞损伤的炎症反应，而关于CAM在动脉粥样硬化早期阶段的研究很少，我们现在建议在CARDIA第7年和第15年收集的储存样本中检测另外7个与CAM相关的生物标志物，并将这些数据与CAM上的CARDIA基因和相关基因相结合，以评估这些生物标志物、影响它们的遗传位点和冠状动脉钙化之间的关系。数据分析将表征凸轮基因模式的预测能力，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。遗传主效应和交互作用对血浆细胞黏附分子浓度和冠状动脉钙化风险的有效性将在动脉粥样硬化(MESA)的多种族研究中重复进行研究。此外，相关SNPs的功能评估将通过计算机和体外分析进行，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，并鼓励针对细胞黏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口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，并将其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。本项目的目的是了解循环黏附分子及其遗传变异与动脉粥样硬化发生发展之间的关系。这项研究的一个主要方面是识别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的方法和新的治疗靶点，从而显著降低心血管疾病的发生率。

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.