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Molecular mechanisms of coronary artery disease risk at the PDGFD locus

Author

Listed:
  • Hyun-Jung Kim

    (Division of Cardiovascular Medicine)

  • Paul Cheng

    (Division of Cardiovascular Medicine)

  • Stanislao Travisano

    (Division of Cardiovascular Medicine)

  • Chad Weldy

    (Division of Cardiovascular Medicine)

  • João P. Monteiro

    (Division of Cardiovascular Medicine)

  • Ramendra Kundu

    (Division of Cardiovascular Medicine)

  • Trieu Nguyen

    (Division of Cardiovascular Medicine)

  • Disha Sharma

    (Division of Cardiovascular Medicine)

  • Huitong Shi

    (Division of Cardiovascular Medicine)

  • Yi Lin

    (Research Center for Intelligent Computing Platforms, Zhejiang Laboratory
    National University of Singapore
    National University of Singapore)

  • Boxiang Liu

    (National University of Singapore
    National University of Singapore)

  • Saptarsi Haldar

    (Amgen Inc.)

  • Simon Jackson

    (Amgen Inc.)

  • Thomas Quertermous

    (Division of Cardiovascular Medicine)

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.

Suggested Citation

  • Hyun-Jung Kim & Paul Cheng & Stanislao Travisano & Chad Weldy & João P. Monteiro & Ramendra Kundu & Trieu Nguyen & Disha Sharma & Huitong Shi & Yi Lin & Boxiang Liu & Saptarsi Haldar & Simon Jackson &, 2023. "Molecular mechanisms of coronary artery disease risk at the PDGFD locus," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36518-9
    DOI: 10.1038/s41467-023-36518-9
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    References listed on IDEAS

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    2. Colin D Mathers & Dejan Loncar, 2006. "Projections of Global Mortality and Burden of Disease from 2002 to 2030," PLOS Medicine, Public Library of Science, vol. 3(11), pages 1-20, November.
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