title: A systems biology framework identifies molecular underpinnings of coronary heart disease.
abstract: OBJECTIVE
  Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene-disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD.
  
  
  RESULTS
  We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. Twenty-four coexpression modules were identified, including 1 case-specific and 1 control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with gene expression-associated single-nucleotide polymorphisms and with results of genome-wide association studies of CHD and its risk factors, the control-specific DM was implicated as CHD causal based on its significant enrichment for both CHD and lipid expression-associated single-nucleotide polymorphisms. This causal DM was further integrated with tissue-specific Bayesian networks and protein-protein interaction networks to identify regulatory key driver genes. Multitissue key drivers (SPIB and TNFRSF13C) and tissue-specific key drivers (eg, EBF1) were identified.
  
  
  CONCLUSIONS
  Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.
authors.affiliation: From the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Huan
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Saixia
authors.initials: S
authors.lastname: Ying
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.forename: Richard
authors.initials: R
authors.lastname: Wang
authors.forename: Poching
authors.initials: P
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Courchesne
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Qingying
authors.initials: Q
authors.lastname: Meng
authors.forename: Christine
authors.initials: C
authors.lastname: Suver
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Jonathan
authors.initials: J
authors.lastname: Derry
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
mesh_terms: D017677:Age Distribution; D000368:Aged; D001499:Bayes Theorem; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D018570:Risk Assessment; D017678:Sex Distribution; D049490:Systems Biology / Q000379:methods*
keywords: coexpression network; coronary heart disease; gene expression; systems biology
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