Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases.
Sylvia T NurnbergMarie A GuerratyRobert C WirkaH Shanker RaoMilos PjanicScott S NortonFelipe SerranoLjubica PerisicSusannah ElwynJohn PlutaWei ZhaoStephanie TestaYoSon ParkTrieu D NguyenYi-An KoTing WangUlf HedinSanjay SinhaYoseph BarashChristopher D BrownThomas QuertermousDaniel James RaderPublished in: PLoS genetics (2020)
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.
Keyphrases
- genome wide
- coronary artery disease
- copy number
- coronary artery
- dna methylation
- poor prognosis
- endothelial cells
- epithelial mesenchymal transition
- binding protein
- pulmonary artery
- genome wide association
- induced apoptosis
- abdominal aortic aneurysm
- percutaneous coronary intervention
- atrial fibrillation
- signaling pathway
- type diabetes
- chronic kidney disease
- genome wide identification
- long non coding rna
- single cell
- cardiovascular disease
- high resolution
- cell proliferation
- small molecule
- coronary artery bypass grafting
- bioinformatics analysis
- pulmonary hypertension
- heart failure
- aortic stenosis
- climate change
- brain injury
- acute coronary syndrome
- protein protein