Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.
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http://dx.doi.org/10.1038/s41586-024-07022-x | DOI Listing |
Adv Sci (Weinh)
January 2025
Tissue Engineering and Organ Manufacturing (TEOM) Lab, Department of Biomedical Engineering, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China.
Liver organoids have been increasingly adopted as a critical in vitro model to study liver development and diseases. However, the pre-vascularization of liver organoids without affecting liver parenchymal specification remains a long-lasting challenge, which is essential for their application in regenerative medicine. Here, the large-scale formation of pre-vascularized human hepatobiliary organoids (vhHBOs) is presented without affecting liver epithelial specification via a novel strategy, namely nonparenchymal cell grafting (NCG).
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January 2025
Vascular Gland Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, Hebei, China.
Previous studies highlighting the pivotal function of the S100A8 protein have shown that inflammation and vascular endothelial harm play a major role in deep vein thrombosis (DVT) development, as evidenced by earlier studies highlighting the pivotal function of the S100 calcium-binding protein A8 (S100A8). Therefore, we aimed to establish a connection between S100A8 and DVT and investigate the role of S100A8 in DVT development. Blood specimens were taken from 23 patients with DVT and 31 controls.
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January 2025
PKUCare Lu'an Hospital, 046204, Shanxi, China.
Periodontitis, a common chronic inflammatory condition caused by bacteria, leads to loss of attachment, resorption of alveolar bone, and ultimately tooth loss. Therefore, reducing bacterial load and fostering alveolar bone regeneration are essential components in the treatment of periodontitis. In this study, we prepared smaller-sized Ag-Metal Organic Frameworks (Ag@MOF) and loaded with sodium alginate (Alg) hydrogel for periodontitis treatment.
View Article and Find Full Text PDFTrends Parasitol
January 2025
Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, Australia; Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, Australia.
In Plasmodium falciparum malaria, infected cells accumulate in blood vessels of organs, including the brain. Recently, Reyes et al. identified monoclonal antibodies that stop infected cells from binding to the endothelial protein C receptor (EPCR) in a model of brain blood vessels.
View Article and Find Full Text PDFJ Thromb Haemost
January 2025
Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
Background: Blood clot formation, triggered by vascular injury, is crucial for haemostasis and thrombosis. Blood clots are composed mainly of fibrin fibres, platelets and red blood cells (RBCs). Recent studies show that clot surface also develops a fibrin film, which provides protection against wound infection and retains components such as RBCs within the clot.
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