1. Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing.
- Author
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Lo Sardo V, Chubukov P, Ferguson W, Kumar A, Teng EL, Duran M, Zhang L, Cost G, Engler AJ, Urnov F, Topol EJ, Torkamani A, and Baldwin KK
- Subjects
- Aged, Aged, 80 and over, Female, HEK293 Cells, Humans, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear pathology, Male, Middle Aged, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle pathology, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Transcription, Genetic, Chromosomes, Human, Pair 9 genetics, Chromosomes, Human, Pair 9 metabolism, Coronary Artery Disease genetics, Coronary Artery Disease metabolism, Coronary Artery Disease pathology, Gene Editing, Haplotypes, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Polymorphism, Single Nucleotide
- Abstract
The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease (CAD), accounting for ∼10%-15% of disease in non-African populations. The ∼60 kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Here, we produce induced pluripotent stem cells (iPSCs) from risk and non-risk individuals, delete each haplotype using genome editing, and generate vascular smooth muscle cells (VSMCs). Risk VSMCs exhibit globally altered transcriptional networks that intersect with previously identified CAD risk genes and pathways, concomitant with aberrant adhesion, contraction, and proliferation. Unexpectedly, deleting the risk haplotype rescues VSMC stability, while expressing the 9p21.3-associated long non-coding RNA ANRIL induces risk phenotypes in non-risk VSMCs. This study shows that the risk haplotype selectively predisposes VSMCs to adopt a cell state associated with CAD phenotypes, defines new VSMC-based networks of CAD risk genes, and establishes haplotype-edited iPSCs as powerful tools for functionally annotating the human genome., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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