Cellular Adhesion Molecules: Genes, Phenotypes, and Coronary Atherosclerosis

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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.