Cellular Adhesion Molecules: Genes, Phenotypes, and Coronary Atherosclerosis

描述（由申请人提供）：细胞粘附分子（CAMs）可能在动脉粥样硬化的发展中起关键作用。可溶性细胞内粘附分子(ICAM)-1与老年人临床冠心病有关，主要在病例对照设计中。在动物研究中已经提出了合理的途径。我们的辅助研究（R01 HL 53560）对年轻人冠状动脉风险发展（CARDIA）研究的初步数据显示，CARDIA第15年（平均年龄40岁）的ICAM-1浓度可预测5年后冠状动脉钙化的发生。此外，来自SeattleSNPs NHLBI基因组应用项目的完整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许多CAMs协同工作，协调血管内皮损伤的炎症反应，并且CAMs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年收集的存储样本中测量7个额外的CAMs相关生物标志物，并将这些数据与CARDIA中CAM和相关基因的基因型相结合，以评估生物标志物之间的关系。影响它们的基因位点和冠状动脉钙化。数据分析将描述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，包括基因-基因和基因-环境相互作用的评估。多民族动脉粥样硬化研究（MESA）将通过复制研究遗传主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，相关snp的功能评估将通过计算机和体外分析进行，以提高我们研究结果的生物学可解释性。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和死亡的主要原因。虽然已经确定了几个主要的危险因素，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确定这些关系。本研究结果可能有助于找到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病率。

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.