Abstract 88: Systems Biology Approaches to Exploring Molecular Mechanisms Underlying Blood Pressure Regulation
Blood pressure (BP) is a complex trait that is influenced by both genetic and environment factors. Recent genome-wide association studies (GWAS) have identified about 30 genetic loci that are associated with systolic and diastolic blood pressure (SBP, DBP) and hypertension. However, the molecular mechanisms underlying the GWAS associations remain unclear. We hypothesize that BP-associated genetic variants with both strong and subtle effects drive shifts in gene subnetworks that in turn affect BP. We surveyed BP-associated molecular interactions in Framingham offspring cohort participants (n=2461; 55% women; age range 40-92 yrs.) by integrating gene expression profiles, expression-associated SNPs (eSNPs), and BP GWAS with network approaches. Peripheral whole blood samples were collected and large-scale transcriptomic microarray analysis was performed on all available participants who attended a clinic visit in 2005-2008. Based on pedigrees the samples were split into a discovery set (n=1421) and a replication set (n=820). The expression levels of 661 genes (FDR < 20%) and the eigengenes of 3 coexpression modules (CoEMs), which were found to be significantly correlated with SBP or DBP in the discovery set, were tested in the replication set. Seventy-two genes were replicated at FDR < 20%. The 72-gene BP-correlated signature and 2 of the three CoEMs were found to be significantly enriched for eSNPs with low p value associations with BP in the International Consortium of Blood Pressure (ICBP) GWAS at p<0.001, suggesting that these gene sets play causal roles in BP regulation. The putative causal BP gene sets were in turn integrated with tissue-specific Bayesian networks and a protein-protein interaction network to identify central network nodes (key drivers or KDs) that drive these BP-related gene sets. One hundred and ten KDs including TSPAN2, ECT2 and KCNK3 were identified. The BP causal gene sets and their KDs are enriched for BP-related biological processes including ion transport, nervous system development, and blood coagulation. Our systems biology analysis not only predicts novel BP risk genes, but also uncovers a network structure that entails the molecular interactions among BP and cardiovascular risk genes in a tissue-specific fashion.
- © 2012 by American Heart Association, Inc.