Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases

Autoři: Sylvia T. Nurnberg aff001;  Marie A. Guerraty aff001;  Robert C. Wirka aff002;  H. Shanker Rao aff001;  Milos Pjanic aff002;  Scott Norton aff003;  Felipe Serrano aff004;  Ljubica Perisic aff005;  Susannah Elwyn aff001;  John Pluta aff001;  Wei Zhao aff001;  Stephanie Testa aff001;  YoSon Park aff003;  Trieu Nguyen aff002;  Yi-An Ko aff003;  Ting Wang aff002;  Ulf Hedin aff005;  Sanjay Sinha aff004;  Yoseph Barash aff003;  Christopher D. Brown aff003;  Thomas Quertermous aff002;  Daniel J. Rader aff001
Působiště autorů: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff001;  Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America aff002;  Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff003;  Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom aff004;  Department of Molecular Medicine and Surgery, Karolinska Institute, Solna, Sweden aff005
Vyšlo v časopise: Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases. PLoS Genet 16(1): e1008538. doi:10.1371/journal.pgen.1008538
Kategorie: Research Article


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.

Klíčová slova:

Arteries – Coronary arteries – Coronary heart disease – Gene expression – Genetic loci – Genome-wide association studies – Smooth muscle cells – Vascular diseases


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