title: Pathway analysis of coronary atherosclerosis.
abstract: Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.
authors.affiliation: Donald W. Reynolds Cardiovascular Research Center, Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University, Stanford, California 94305, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: King
authors.forename: Rossella
authors.initials: R
authors.lastname: Ferrara
authors.forename: Raymond
authors.initials: R
authors.lastname: Tabibiazar
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Mary M
authors.initials: MM
authors.lastname: Chen
authors.forename: Allan
authors.initials: A
authors.lastname: Kuchinsky
authors.forename: Aditya
authors.initials: A
authors.lastname: Vailaya
authors.forename: Robert
authors.initials: R
authors.lastname: Kincaid
authors.forename: Anya
authors.initials: A
authors.lastname: Tsalenko
authors.forename: David Xing-Fei
authors.initials: DX
authors.lastname: Deng
authors.forename: Andrew
authors.initials: A
authors.lastname: Connolly
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Eugene
authors.initials: E
authors.lastname: Yang
authors.forename: Clifton
authors.initials: C
authors.lastname: Watt
authors.forename: Zohar
authors.initials: Z
authors.lastname: Yakhini
authors.forename: Amir
authors.initials: A
authors.lastname: Ben-Dor
authors.forename: Annette
authors.initials: A
authors.lastname: Adler
authors.forename: Laurakay
authors.initials: L
authors.lastname: Bruhn
authors.forename: Philip
authors.initials: P
authors.lastname: Tsao
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D003198:Computer Simulation; D003324:Coronary Artery Disease / Q000473:pathology*; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D007107:Immune System; D007150:Immunohistochemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D017202:Myocardial Ischemia / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D049490:Systems Biology
chemical_list: D018076:DNA, Complementary; D012313:RNA