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

Abstract

Central IllustrationALK1 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.

Genome‐wide in vitro and in vivo RNAi screens reveal Fer3 to be an important regulator of kkv transcription in Drosophila

“…RNAi high‐throughput screening is a genome‐wide research method based on RNAi technology. In the past 20 years, many scientists have applied this technique to study diverse cellular processes in Drosophila and mammalian cells cultured in vitro , including signal transduction, tumor biology, virology, host cell response after infection, and diverse disease‐related processes (Campeau & Gobeil, 2011; Mohr et al ., 2010; Nanda et al ., 2017). The results of these studies have not only identified new components of these metabolic processes but also broadened our understanding of these complex biological processes.…”