Multimodal CRISPR perturbations of GWAS loci associated with coronary artery disease in vascular endothelial cells.

ABSTRACT: Genome-wide association studies have identified >250 genetic variants associated with coronary artery disease (CAD), but the causal variants, genes and molecular mechanisms remain unknown at most loci. We performed pooled CRISPR screens to test the impact of sequences at or near CAD-associated genetic variants on vascular endothelial cell functions. Using CRISPR knockout, inhibition and activation, we targeted 1998 variants at 83 CAD loci to assess their effect on three adhesion proteins (E-selectin, ICAM1, VCAM1) and three key endothelial functions (nitric oxide and reactive oxygen species production, calcium signalling). At a false discovery rate ≤10%, we identified significant CRISPR perturbations near 42 variants located within 26 CAD loci. We used base editing to validate a putative c

SUBMITTER: Wunnemann F 

PROVIDER: S-EPMC10047545 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature