Format

Send to

Choose Destination
Cell. 2018 Dec 13;175(7):1796-1810.e20. doi: 10.1016/j.cell.2018.11.014. Epub 2018 Dec 6.

Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing.

Author information

1
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093-0412, USA.
3
Sangamo BioSciences, Inc., Richmond, CA 94804-3517, USA.
4
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093-0412, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
5
Scripps Research Translational Institute, The Scripps Research Institute, La Jolla, CA, 92037, USA; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, CA.
6
Scripps Research Translational Institute, The Scripps Research Institute, La Jolla, CA, 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
7
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: kbaldwin@scripps.edu.

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.

KEYWORDS:

arterial wall; cardiovascular disease; coronary artery; disease modeling; genome editing; iPSCs; lncRNA; stem cells; vascular smooth muscle cells

PMID:
30528432
PMCID:
PMC6346426
[Available on 2019-12-13]
DOI:
10.1016/j.cell.2018.11.014

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center