title: Signature patterns of gene expression in mouse atherosclerosis and their correlation to human coronary disease.
abstract: The propensity for developing atherosclerosis is dependent on underlying genetic risk and varies as a function of age and exposure to environmental risk factors. Employing three mouse models with different disease susceptibility, two diets, and a longitudinal experimental design, it was possible to manipulate each of these factors to focus analysis on genes most likely to have a specific disease-related function. To identify differences in longitudinal gene expression patterns of atherosclerosis, we have developed and employed a statistical algorithm that relies on generalized regression and permutation analysis. Comprehensive annotation of the array with ontology and pathway terms has allowed rigorous identification of molecular and biological processes that underlie disease pathophysiology. The repertoire of atherosclerosis-related immunomodulatory genes has been extended, and additional fundamental pathways have been identified. This highly disease-specific group of mouse genes was combined with an extensive human coronary artery data set to identify a shared group of genes differentially regulated among atherosclerotic tissues from different species and different vascular beds. A small core subset of these differentially regulated genes was sufficient to accurately classify various stages of the disease in mouse. The same gene subset was also found to accurately classify human coronary lesion severity. In addition, this classifier gene set was able to distinguish with high accuracy atherectomy specimens from native coronary artery disease vs. those collected from in-stent restenosis lesions, thus identifying molecular differences between these two processes. These studies significantly focus efforts aimed at identifying central gene regulatory pathways that mediate atherosclerotic disease, and the identification of classification gene sets offers unique insights into potential diagnostic and therapeutic strategies in atherosclerotic disease.
authors.affiliation: Donald W. Reynolds Cardiovascular Clinical Research Center, Division of Cardiovascular Medicine, Stanford, CA, USA. rtabibiazar@cvmed.stanford.edu
authors.forename: Raymond
authors.initials: R
authors.lastname: Tabibiazar
authors.forename: Roger A
authors.initials: RA
authors.lastname: Wagner
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: King
authors.forename: Rossella
authors.initials: R
authors.lastname: Ferrara
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: David A
authors.initials: DA
authors.lastname: Sanan
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Narasimhan
authors.forename: Robert
authors.initials: R
authors.lastname: Tibshirani
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
authors.forename: Bradley
authors.initials: B
authors.lastname: Efron
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics*; D003327:Coronary Disease / Q000235:genetics*; D003331:Coronary Vessels / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D015203:Reproducibility of Results; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics
chemical_list: D001057:Apolipoproteins E