Molecular mechanisms of coronary artery disease risk at the PDGFD locus

Abstract

Genome wide association studies for coronary artery disease (CAD) have identified a risk locus at 11q22.3. Here, we verify with mechanistic studies that rs2019090 and PDGFD represent the functional variant and gene at this locus. Further, FOXC1/C2 transcription factor binding at rs2019090 is shown to promote PDGFD transcription through the CAD promoting allele. With single cell transcriptomic and histology studies with Pdgfd knockdown in an SMC lineage tracing male atherosclerosis mouse model we find that Pdgfd promotes expansion, migration, and transition of SMC lineage cells to the chondromyocyte phenotype. Pdgfd also increases adventitial fibroblast and pericyte expression of chemokines and leukocyte adhesion molecules, which is linked to plaque macrophage recruitment. Despite these changes there is no effect of Pdgfd deletion on overall plaque burden. These findings suggest that PDGFD mediates CAD risk by promoting deleterious phenotypic changes in SMC, along with an inflammatory response that is primarily focused in the adventitia.

Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk

“…For instance, smooth muscle cell (SMC) CAD causal gene PDGFD was found to be regulated in an allele-specific fashion by a causal variant that modulated FOXC (forkhead box) factor binding. 9 Interestingly, FOXC1 and FOXC2 both reside in GWAS CAD loci and are known to be critical for arterial development.…”

“…For instance, smooth muscle cell (SMC) CAD causal gene PDGFD was found to be regulated in an allele-specific fashion by a causal variant that modulated FOXC (forkhead box) factor binding. 9 Interestingly, FOXC1 and FOXC2 both reside in GWAS CAD loci and are known to be critical for arterial development. In some cases, it is difficult or impossible to target all candidate variants in linkage disequilibrium in an associated locus, and alteration of an entire enhancer region can be used.…”

“…This is exemplified by recent studies investigating the mechanism of disease causality for the CAD gene PDGFD . 9 These studies showed this CAD gene promotes the SMC chondromyocyte phenotype, vascular calcification, macrophage content, and general inflammatory profile in the plaque and adventitia. These traits that have all been identified as high-probability mechanisms by which plaque is destabilized to promote myocardial infarction.…”

“…A striking feature of a number of the CAD genes studied in this and other laboratories indicates that extensive cell state changes can occur in the plaque cells without producing an obvious change in plaque volume. 9,17,20,21 A failure to find changes in lesion size for a CAD gene knockout does not mean that the gene is not causal and not important for the initiation or expansion of disease and thus disease risk. For genes in CAD loci identified through characterization of the causal variant and linking that variant to the causal gene through transcriptional and epigenetic studies firmly establish causality.…”

“…For instance, this laboratory has collaborated with Amgen to investigate the possible therapeutic effect of blocking the CAD-associated gene PDGFD in a murine model. 9…”