TY - JOUR
T1 - Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease
AU - Tay, Kai Yi
AU - Wu, Kan Xing
AU - Chioh, Florence Wen Jing
AU - Autio, Matias Ilmari
AU - Pek, Nicole Min Qian
AU - Narmada, Balakrishnan Chakrapani
AU - Tan, Sock Hwee
AU - Low, Adrian Fatt Hoe
AU - Lian, Michelle Mulan
AU - Chew, Elaine Guo Yan
AU - Lau, Hwee Hui
AU - Kao, Shih Ling
AU - Teo, Adrian Kee Keong
AU - Foo, Jia Nee
AU - Foo, Roger Sik Yin
AU - Heng, Chew Kiat
AU - Chan, Mark Yan Yee
AU - Cheung, Christine
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/12
Y1 - 2022/12
N2 - Background and aims: Single nucleotide polymorphism rs6903956 has been identified as one of the genetic risk factors for coronary artery disease (CAD). However, rs6903956 lies in a non-coding locus on chromosome 6p24.1. We aim to interrogate the molecular basis of 6p24.1 containing rs6903956 risk alleles in endothelial disease biology. Methods and Results: We generated induced pluripotent stem cells (iPSCs) from CAD patients (AA risk genotype at rs6903956) and non-CAD subjects (GG non-risk genotype at rs6903956). CRISPR-Cas9-based deletions (Δ63-89bp) on 6p24.1, including both rs6903956 and a short tandem repeat variant rs140361069 in linkage disequilibrium, were performed to generate isogenic iPSC-derived endothelial cells. Edited CAD endothelial cells, with removal of ‘A’ risk alleles, exhibited a global transcriptional downregulation of pathways relating to abnormal vascular physiology and activated endothelial processes. 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. Conclusions: Our study reveals the trans-acting impact of 6p24.1 with another CAD locus on 10q11.21 and is associated with intensified endothelial injury.
AB - Background and aims: Single nucleotide polymorphism rs6903956 has been identified as one of the genetic risk factors for coronary artery disease (CAD). However, rs6903956 lies in a non-coding locus on chromosome 6p24.1. We aim to interrogate the molecular basis of 6p24.1 containing rs6903956 risk alleles in endothelial disease biology. Methods and Results: We generated induced pluripotent stem cells (iPSCs) from CAD patients (AA risk genotype at rs6903956) and non-CAD subjects (GG non-risk genotype at rs6903956). CRISPR-Cas9-based deletions (Δ63-89bp) on 6p24.1, including both rs6903956 and a short tandem repeat variant rs140361069 in linkage disequilibrium, were performed to generate isogenic iPSC-derived endothelial cells. Edited CAD endothelial cells, with removal of ‘A’ risk alleles, exhibited a global transcriptional downregulation of pathways relating to abnormal vascular physiology and activated endothelial processes. 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. Conclusions: Our study reveals the trans-acting impact of 6p24.1 with another CAD locus on 10q11.21 and is associated with intensified endothelial injury.
KW - Chemokine
KW - Coronary artery disease
KW - Endothelial cell disease models
KW - Long-range chromatin interaction
KW - Single nucleotide polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=85142361351&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85142361351&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2022.10.012
DO - 10.1016/j.atherosclerosis.2022.10.012
M3 - Article
C2 - 36435092
AN - SCOPUS:85142361351
SN - 0021-9150
VL - 362
SP - 11
EP - 22
JO - Atherosclerosis
JF - Atherosclerosis
ER -