A systems biology framework identifies molecular underpinnings of coronary heart disease.
Arterioscler Thromb Vasc Biol
; 33(6): 1427-34, 2013 Jun.
Article
in En
| MEDLINE
| ID: mdl-23539213
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. APPROACH ANDRESULTS:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Coronary Artery Disease
/
Gene Expression Regulation
/
Genetic Predisposition to Disease
/
Systems Biology
/
Gene Regulatory Networks
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Arterioscler Thromb Vasc Biol
Journal subject:
ANGIOLOGIA
Year:
2013
Type:
Article
Affiliation country:
United States