The Intersection of Genome-Wide Association Studies and High-Throughput Small Interfering Ribonucleic Acid Screens Allows for the Identification of Novel Pathways Relevant to Atherosclerosis

Central Illustration ALK1 Mediates LDL Uptake and Transcytosis in Endothelial Cells (A) Genome-wide ribonucleic acid interference screen targeting over 18,000 genes in cultured endothelial cells (ECs), and publicly available genome wide association studies (GWAS) reveal activin-like kinase 1 (ALK1) as an EC-specific low density lipoprotein (LDL)–binding protein responsible for mediating LDL uptake and transcytosis. (B) Proposed mechanism showing that in conditions of hypercholesterolemia, ALK1 binds LDL particles, which are then internalized by ECs via an endocytic pathway that prevents LDL from lysosomal degradation, consequently resulting in enhanced LDL transcytosis. LDLR = low-density lipoprotein receptor; siRNA = small interfering ribonucleic acid.