Identification of Risk Pathways and Functional Modules for Coronary Artery Disease Based on Genome-Wide SNP Data

Abstract

Coronary artery disease (CAD) is a complex human disease, involving multiple genes and their nonlinear interactions, which often act in a modular fashion. Genome-wide single nucleotide polymorphism (SNP) profiling provides an effective technique to unravel these underlying genetic interplays or their functional involvements for CAD. This study aimed to identify the susceptible pathways and modules for CAD based on SNP omics. First, the Wellcome Trust Case Control Consortium (WTCCC) SNP datasets of CAD and control samples were used to assess the joint effect of multiple genetic variants at the pathway level, using logistic kernel machine regression model. Then, an expanded genetic network was constructed by integrating statistical gene–gene interactions involved in these susceptible pathways with their protein–protein interaction (PPI) knowledge. Finally, risk functional modules were identified by decomposition of the network. Of 276 KEGG pathways analyzed, 6 pathways were found to have a significant effect on CAD. Other than glycerolipid metabolism, glycosaminoglycan biosynthesis, and cardiac muscle contraction pathways, three pathways related to other diseases were also revealed, including Alzheimer’s disease, non-alcoholic fatty liver disease, and Huntington’s disease. A genetic epistatic network of 95 genes was further constructed using the abovementioned integrative approach. Of 10 functional modules derived from the network, 6 have been annotated to phospholipase C activity and cell adhesion molecule binding, which also have known functional involvement in Alzheimer’s disease. These findings indicate an overlap of the underlying molecular mechanisms between CAD and Alzheimer’s disease, thus providing new insights into the molecular basis for CAD and its molecular relationships with other diseases.

Exome-Wide Association Study Reveals Several Susceptibility Genes and Pathways Associated With Acute Coronary Syndromes in Han Chinese

“…The six top-ranking pathways were cyclin-dependent protein serine/threonine kinase inhibitor activity, RIG-I-like receptor signaling pathway, organophosphate ester transport, negative regulation of muscle cell differentiation, phospholipid efflux, and phospholipid transport (Figure 2). Several previously reported pathways were also replicated in our study, including low-density lipoprotein particle receptor binding, positive regulation of triglyceride metabolic process, reverse cholesterol transport, and lipoprotein metabolic pathways (Makinen et al, 2014;Ghosh et al, 2015;Zhao et al, 2016).…”

“…KLFs have been shown to interact with the components of atherosclerosis pathogenesis and have also been linked to metabolic abnormalities, including obesity and diabetes mellitus (Pollak et al, 2018). In line with our findings from KEGG enrichment analysis of co-expressed genes of ZNF655, Zhao et al (2016) constructed a genetic network based on gene-gene interactions and revealed that pathways involved in Alzheimer's disease, non-alcoholic fatty liver disease, and Huntington's disease were also associated with CAD risk. Moreover, Bis et al (2018) recently identified the importance of ZNF655 for transcriptional regulation in Alzheimer's disease pathogenesis through whole genome sequencing.…”

The GEnetic Syntax Score: a genetic risk assessment implementation tool grading the complexity of coronary artery disease—rationale and design of the GESS study

“…Furthermore, Liu et al reported that the most studied multi-loci genes are those of angiotensin I converting enzyme, lipid and lipoprotein metabolism [ 1 ]. Hence, individual GWAS and meta-analyses have confirmed the speculated deterministic role of genetic predisposition in occurrence, progression of atherosclerosis and coronary plaque calcification, with multiple converging pathways, including cardiac muscle contraction, glycerolipid metabolism, and glycosaminoglycan biosynthesis [ 5 , 32 , 37 , 40 ].…”

Changes of protein levels in human urine reflect the dysregulation of signaling pathways of chronic kidney disease and its complications

“…In addition, we also found similar changes of COX7B, COX6A2 and UQCRQ also exist in the cardiac muscle contraction pathway. An abnormal cardiac muscle contraction pathway has a significant effect on coronary artery disease as well as cardiac hypertrophy and dysfunction 23 , 24 . The three overlapping proteins in these two pathways also provide evidence that CKD and cardiovascular disease may have some commonalities in pathogenesis.…”