Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases.
Authors
Pjanic, Milos
Serrano, Felipe
Perisic, Ljubica
Elwyn, Susannah
Testa, Stephanie
Ko, Yi-An
Wang, Ting
Publication Date
2020-01Journal Title
PLoS Genet
ISSN
1553-7390
Publisher
Public Library of Science (PLoS)
Volume
16
Issue
1
Pages
e1008538
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Nurnberg, S. T., Guerraty, M. A., Wirka, R. C., Rao, H. S., Pjanic, M., Norton, S., Serrano, F., et al. (2020). Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases.. PLoS Genet, 16 (1), e1008538. https://doi.org/10.1371/journal.pgen.1008538
Abstract
Genome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses. We identified sQTLs for TARS2, YAP1, CFDP1, and STAT6 in HCASMCs and HCAECs, and 233 ASE genes, a subset of which are also GTEx eGenes in arterial tissues. Colocalization of GWAS association signals for coronary artery disease (CAD), migraine, stroke and abdominal aortic aneurysm with GTEx eGenes in aorta, coronary artery and tibial artery discovered novel candidate risk genes for these diseases. At the CAD and stroke locus tagged by rs2107595 we demonstrate colocalization with expression of the proximal gene TWIST1. We show that disrupting the rs2107595 locus alters TWIST1 expression and that the risk allele has increased binding of the NOTCH signaling protein RBPJ. Finally, we provide data that TWIST1 expression influences vascular SMC phenotypes, including proliferation and calcification, as a potential mechanism supporting a role for TWIST1 in CAD.
Keywords
Coronary Vessels, Endothelium, Vascular, Cells, Cultured, Endothelial Cells, Myocytes, Smooth Muscle, Humans, Vascular Diseases, Nuclear Proteins, Protein Binding, Polymorphism, Single Nucleotide, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Transcriptome, Twist-Related Protein 1
Sponsorship
British Heart Foundation (RG/17/5/32936)
Medical Research Council (MC_PC_12009)
British Heart Foundation (FS/18/46/33663)
Medical Research Council (MC_PC_17230)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1371/journal.pgen.1008538
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299435
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