Associations of genetic variation and mRNA expression of PDGF/PDGFRB pathway genes with coronary artery disease in the Chinese population.

Abstract

Platelet-derived growth factors (PDGFs) and receptors (PDGFR) play a key role in the process of coronary atherosclerosis. We aimed to investigate the association of genetic variations and mRNA expressions of PDGF/PDGFRB pathway genes with coronary artery disease (CAD). In this case-control study (3139 CAD vs. 3270 controls), 13 single nucleotide polymorphisms (SNPs) at five pathway genes were genotyped and combined to construct a weighted genetic risk score (wGRS). Three hundred and six pairs of cases and controls were selected for mRNA quantification. Restricted cubic spline (RCS) analyses were conducted for the dose-response relationship between wGRS, mRNAs and CAD. Area under the curve (AUC) was estimated to evaluate the discrimination of wGRS, mRNAs, and traditional risk factors (TRF) for CAD. The wGRS exhibited a positive linear relationship with CAD (p for linearity <0.001), and the medium and high wGRS had 37% and 50% increased risk of CAD compared to the low wGRS group (p = 1.5 × 10^-4; p = 5.7 × 10^-5). mRNA expression levels of five genes in peripheral blood leukocytes were all lower among patients at admission than controls (p < 0.001). The PDGF/PDGFRB mRNA expressions had significant non-linear correlations with AMI, with "U"-shaped trend for PDGFA, PDGFB and "L"-shaped trend for PDGFC, PDGFD and PDGFRB. Adding wGRS and mRNAs to the TRF model significantly improved the discrimination for CAD with an AUC of 0.921 (95% CI, 0.898-0.943). Genetic variations in the PDGF/PDGFRB pathway contribute to CAD susceptibility with a significantly joint effect. The down-regulated PDGF/PDGFRB mRNAs in peripheral leukocytes have the potential as blood-based biomarkers for CAD with high discriminative value.