Beschreibung:
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>PDGFD</jats:italic> represent the functional variant and gene at this locus. Further, FOXC1/C2 transcription factor binding at rs2019090 is shown to promote <jats:italic>PDGFD</jats:italic> transcription through the CAD promoting allele. With single cell transcriptomic and histology studies with <jats:italic>Pdgfd</jats:italic> 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 <jats:italic>Pdgfd</jats:italic> deletion on overall plaque burden. These findings suggest that <jats:italic>PDGFD</jats:italic> mediates CAD risk by promoting deleterious phenotypic changes in SMC, along with an inflammatory response that is primarily focused in the adventitia.</jats:p>