Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease

Tay, K. Y.; Wu, K. X.; Chioh, F.; Autio, M. I.; Pek, N.; Chakrapani, N. B.; Tan, S. H.; Low, A.; Lian, M. M.; Chew, E. G. Y.; Lau, H. H.; Kao, S. L.; Teo, A.; Foo, J. N.; Foo, R.; Heng, C. K.; Chan, M.; Cheung, C.

doi:10.1101/2022.07.12.499721

bioRxiv · 10.1101/2022.07.12.499721

Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease

Tay, K. Y.·Wu, K. X.·Chioh, F.·Autio, M. I.·Pek, N.·Chakrapani, N. B.·Tan, S. H.·Low, A.·Lian, M. M.·Chew, E. G. Y.·Lau, H. H.·Kao, S. L.·Teo, A.·Foo, J. N.·Foo, R.·Heng, C. K.·Chan, M.·Cheung, C.

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Abstract

Background and AimsSingle 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 ResultsWe generated 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 ({Delta}63-89bp) 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. ConclusionOur study reveals the trans-acting impact of 6p24.1 with another CAD locus on 10q11.21 and is associated with intensified endothelial injury.

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Tay, K. Y., Wu, K. X., Chioh, F., Autio, M. I., Pek, N., Chakrapani, N. B., Tan, S. H., Low, A., Lian, M. M., Chew, E. G. Y., Lau, H. H., Kao, S. L., Teo, A., Foo, J. N., Foo, R., Heng, C. K., Chan, M., Cheung, C.. 2022-07-13. Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease. https://doi.org/10.1101/2022.07.12.499721

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