Coronary artery disease is the primary cause of death in the United States. Treatments such as statins, which focus on reducing high cholesterol levels, can lower the risk of death from coronary artery disease. Statins' impact is, in part, attributed to enhancing blood vessel health. Nevertheless, there is a shortage of treatments that specifically target the endothelial cells lining blood vessels and affecting blood circulation. Pinpointing genetic risk factors linked to endothelial cell performance could aid in creating medications that zero in on blood vessels. Studies have revealed that particular genetic variations are tied to a heightened risk of coronary artery disease. These genetic variations manage the activity of multiple genes that collaborate in a limited number of crucial biological pathways. However, challenges in methodology have hindered the discovery of primary pathways connected to coronary artery disease variants. A recent study utilizing a mix of high-throughput molecular biology approaches and computational techniques has pinpointed significant biological pathways and new genes involved in endothelial cell function that could contribute to the risk of coronary artery disease. The study's findings are featured in Nature. Dr. Jesse Engreitz, an assistant professor at Stanford University, CA, who led the study, explained that genetic risk factors for coronary artery disease converge on a specific pathway in endothelial cells. This pathway is recognized for adjusting endothelial cell reactions to blood flow and comprises genes that could be promising targets for treatments honing in on blood vessels. Additionally, a previously overlooked gene, TLNRD1, was discovered to play a pivotal role in this pathway in both humans and zebrafish. The roster of identified genes may aid in identifying individuals with a genetic inclination towards poor vascular health who may respond better to existing medications.
Researchers have identified genetic risk factors for heart disease through genome-wide association studies. These studies involve analyzing genomes from a large number of individuals to find specific genetic variants linked to the disease. These variants are thought to regulate biological pathways that involve multiple genes working together. Despite progress in identifying genetic variants, connecting them to key biological pathways has been a challenge. Many of these variants do not code for proteins but instead control the expression of nearby genes involved in disease-related pathways. Pinpointing the exact genes influenced by each variant and their role in disease pathways remains difficult. Furthermore, disease development involves various cells with different biological pathways contributing to the condition. Understanding the specific pathways affected by disease-related variants in different cell types is still incomplete. Overall, there is a gap in knowledge regarding how genetic variants identified through genome-wide studies impact biological functions. Current research focuses on investigating the pathways associated with genetic variants linked to coronary artery disease, aiming to uncover valuable insights for disease treatment and management.
254 genes have been associated with coronary artery disease. A recent study analyzed genetic variants linked to coronary artery disease and their impact on blood vessel cells and liver hepatocytes. Specifically focusing on endothelial cells within blood vessel walls, researchers used genetically modified endothelial cells from the human aorta for their analysis. The genome of these cells was sequenced, and a computational model was utilized to identify genes affected by coronary artery disease-associated variants. Nearly 2,000 genes near these variants were identified, with 254 genes showing regulated expression. The study also investigated various programs and pathways related to coronary artery disease by using CRISPR interference to inhibit gene expression and examining resulting changes in endothelial cell gene profiles. Through this analysis, researchers identified 50 coregulated genes forming biological programs, some unrelated to endothelial cells or coronary artery disease. Further examination revealed five programs enriched with the 254 coronary artery disease-associated genes and 43 variants, including genes not previously linked to the condition. These programs were found to be regulated by genes associated with cerebral cavernous malformations (CCM), a brain blood vessel disorder. Notably, the CCM pathway genes, including CCM2, were involved in all five coronary artery disease-related pathways. The study highlighted the potential role of CCM pathway genes in coronary artery disease development. The research also explored a novel gene, TLNRD1, within the CCM pathway, showing it to be a significant regulator of coronary artery disease pathways. Interaction between TLNRD1 and CCM2 was observed, impacting endothelial cell barrier function. Disruption of TLNRD1 expression in zebrafish models affected heart and blood vessel development, suggesting its involvement in cardiovascular diseases. In addition to shedding light on coronary artery disease genetics, the study's methodology could aid in uncovering pathways related to other diseases. By leveraging CRISPR tools to manipulate gene expression in endothelial cells and employing computational models to identify gene interactions, the research team identified potential causal genes for a significant portion of coronary artery disease loci. This novel approach has the potential to revolutionize genetic research across various heritable diseases, impacting future therapeutic strategies and clinical outcomes.
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