|
| Status |
Public on Nov 02, 2022 |
| Title |
Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The variant rs6903956 has been identified as one of the Asian-specific genetic risk factors for coronary artery disease (CAD). However, rs6903956 lies in a non-coding locus on chromosome 6p24.1, hampering efforts of functional annotation. We produced induced pluripotent stem cells (iPSCs) from CAD patients (AA risk genotype at rs6903956) and normal controls (GG non-risk genotype at rs6903956). CRIPSR-Cas9-based deletions (Δ63-89bp) on 6p24.1 including rs6903956 were performed to generate isogenic iPSC-derived endothelial cells. Edited CAD endothelial cells exhibited a global transcriptional downregulation of pathways relating to abnormal vascular physiology and activated endothelial processes. Surprisingly, deletions on either risk or non-risk 6p24.1 locus had minimal influence on cis gene expressions. Instead, a CXC chemokine ligand on chromosome 10q11.21, CXCL12, was uncovered as a potential effector gene in CAD endothelial cells. Underlying this effect was the preferential inter-chromosomal interaction of 6p24.1 risk locus to a weak promoter of CXCL12, confirmed by chromatin conformation capture assays on our iPSC-derived endothelial cells. Functionally, risk genotypes AA/ AG at rs6903956 were associated significantly with elevated levels of circulating damaged endothelial cells in CAD patients. Circulating endothelial cells isolated from patients with risk genotypes AA/ AG were also found to have 10 folds higher CXCL12 transcript copies/ cell than those with non-risk genotype GG. Our study reveals the trans-acting impact of 6p24.1 risk locus, involving the atherosclerosis-implicated gene CXCL12, and is associated with intensified endothelial injury.
|
| |
|
| Overall design |
RNA-seq of endothelial cells differentiated from patient derived induced pluripotent stem cells (iPSCs) with CRISPR-Cas9 based deletions (63-89bp) on 6p24.1 including rs6903956
|
| |
|
| Contributor(s) |
Tay KY, Cheung C |
| Citation(s) |
36435092 |
| |
| Submission date |
Jan 28, 2022 |
| Last update date |
Feb 02, 2023 |
| Contact name |
Christine Cheung |
| E-mail(s) |
ccheung@ntu.edu.sg, KAIYI002@e.ntu.edu.sg
|
| Organization name |
Nanyang Technological University
|
| Street address |
Experimental Medicine Building 59 Nanyang Drive, Level 3
|
| City |
Singapore |
| State/province |
Singapore |
| ZIP/Postal code |
636921 |
| Country |
Singapore |
| |
|
| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
|
| Samples (27)
|
|
| Relations |
| BioProject |
PRJNA801634 |
Less...
More...