Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing.
Cell
; 175(7): 1796-1810.e20, 2018 12 13.
Article
in En
| MEDLINE
| ID: mdl-30528432
The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease (CAD), accounting for â¼10%-15% of disease in non-African populations. The â¼60 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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Chromosomes, Human, Pair 9
/
Coronary Artery Disease
/
Haplotypes
/
Polymorphism, Single Nucleotide
/
Induced Pluripotent Stem Cells
/
Gene Editing
Type of study:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Cell
Year:
2018
Type:
Article
Affiliation country:
United States