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A Systems Biology Framework Identifies Molecular Underpinnings of Coronary Heart Disease

2013; Lippincott Williams & Wilkins; Volume: 33; Issue: 6 Linguagem: Inglês

10.1161/atvbaha.112.300112

1524-4636

Tianxiao Huan, Bin Zhang, Zhi Wang, Roby Joehanes, Jun Zhu, Andrew D. Johnson, Saixia Ying, Peter J. Munson, Nalini Raghavachari, Richard Wang, Poching Liu, Paul Courchesne, Shih‐Jen Hwang, Themistocles L. Assimes, Ruth McPherson, Nilesh J. Samani, Heribert Schunkert, Qingying Meng, Christine Suver, Christopher J. O’Donnell, Jonathan M.J. Derry, Xia Yang, Daniel Levy,

Genetic Associations and Epidemiology

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 and 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.