Molecular mechanisms of coronary artery disease risk at the PDGFD locus.
Molecular mechanisms of coronary artery disease risk at the PDGFD locus.
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DOI：
10.1038/s41467-023-36518-9
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发表时间：
2023-02-15
影响因子：
16.6
通讯作者：
Quertermous, Thomas
中科院分区：
文献类型：
--
作者：
Kim, Hyun-Jung;Cheng, Paul;Travisano, Stanislao;Weldy, Chad;Monteiro, Joao P.;Kundu, Ramendra;Nguyen, Trieu;Sharma, Disha;Shi, Huitong;Lin, Yi;Liu, Boxiang;Haldar, Saptarsi;Jackson, Simon;Quertermous, Thomas
冠状动脉疾病（CAD）的全基因组关联研究已经确定了11q22.3的危险位点。在这里，我们通过机制研究验证了rs2019090和PDGFD代表了该位点的功能变体和基因。此外，FOXC1/C2转录因子结合rs2019090位点，通过CAD促进等位基因促进PDGFD转录。通过在SMC谱系追踪男性动脉粥样硬化小鼠模型中Pdgfd敲低的单细胞转录组学和组织学研究，我们发现Pdgfd促进SMC谱系细胞的扩张、迁移和向软骨细胞表型的转变。Pdgfd还增加了上皮成纤维细胞和周细胞趋化因子和白细胞粘附分子的表达，这与斑块巨噬细胞募集有关。尽管有这些变化，Pdgfd缺失对总体斑块负担没有影响。这些发现表明，PDGFD通过促进SMC的有害表型变化以及主要集中在外膜的炎症反应来介导CAD风险。基因编码冠心病的风险，确定它们的功能对开发新疗法至关重要。在工作报告中，作者已经确定了一个罪魁祸首基因PDGFD，并研究了它是如何提高疾病风险的。
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. Genes encode risk for coronary disease, identifying how they function is critical to developing new therapies. In work reported the authors have identified one culprit gene, PDGFD, and studied how it functions to promote disease risk.
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影响因子：
30.8
作者：
Klarin D;Zhu QM;Emdin CA;Chaffin M;Horner S;McMillan BJ;Leed A;Weale ME;Spencer CCA;Aguet F;Segrè AV;Ardlie KG;Khera AV;Kaushik VK;Natarajan P;CARDIoGRAMplusC4D Consortium;Kathiresan S
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Kathiresan S
影响因子：
37.8
作者：
Cheng P;Wirka RC;Shoa Clarke L;Zhao Q;Kundu R;Nguyen T;Nair S;Sharma D;Kim HJ;Shi H;Assimes T;Brian Kim J;Kundaje A;Quertermous T
通讯作者：
Quertermous T
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
30.8
作者：
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通讯作者：
Samani, Nilesh J.