Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease

Abstract

Coronary artery disease (CAD) is one of the leading threats to global health. Previous research has proven that metabolic pathway disorders, such as high blood lipids and diabetes, are one of the risk factors that mostly cause CAD. However, the crosstalk between metabolic pathways and CAD was mostly studied on physiology processes by analyzing a single gene function. A canonical correlation analysis was used to identify the metabolic pathways, which were integrated as a unit to coexpress with CAD susceptibility genes, and to resolve additional metabolic factors that are related to CAD. Seven pathways, including citrate cycle, ubiquinone, terpenoid quinone biosynthesis, and N-glycan biosynthesis, were identified as an integrated unit coexpressed with CAD genes. These pathways could not be revealed as a coexpressed pathway through traditional methods as each single gene has weak correlation. Furthermore, sets of genes in these pathways were candidate markers for diagnosis and detection from patients' serum.

Figure 1

Strategy of study for the canonical correlation analysis. Collection of CAD genes and metabolic pathway genes; construction of the coexpression network among individual CAD and metabolic pathway genes; performance of CCA; and analysis of canonical variables.

Figure 2

Coexpression network of CAD genes and metabolic pathway genes. The connection indicates the Pearson correlation factor r > 0.6.

Figure 3

PPI network of CAD genes. Note that no metabolic pathway was enriched in the PPI network.

Figure 4

Characteristic of canonical variables indicating integrate pathway. A threshold was set to identify the CCA which cover whole pathway (S_a, S_b > 0.2, r values > 0.5, and P values < 0.001). (a) Scatter plots of seven CCA pairs with top r values. Note that all identified CCA were highly correlated. (b) The coefficient of metabolic pathway genes on seven canonical variables. Each metabolic pathway contains different number of genes. The genes with big values contributed more in CCA. (c) The coefficient of CAD genes on seven canonical variables. The genes with big values contributed more in CCA.

Figure 5

qRT-PCR of metabolic pathway genes in CAD patients. (a) 2583 (B4GALNT1), 2720 (GLB1), and 3074 (HEXB) in glycosphingolipid biosynthesis. (b) 27235 (COQ2), 84274 (COQ5), and 79001 (vkorc1) in ubiquinone and other terpenoid quinone biosyntheses.