Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease
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 al...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/165614 |
| _version_ | 1826125461063729152 |
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| author | Tay, Kai Yi Wu, Kan Xing Chioh, Florence Wen Jing Autio, Matias Ilmari Pek, Nicole Min Qian Narmada, Balakrishnan Chakrapani Tan, Sock-Hwee Low, Adrian Fatt-Hoe Lian, Michelle Mulan Chew, Elaine Guo Yan Lau, Hwee Hui Kao, Shih Ling Teo, Adrian Kee Keong Foo, Jia Nee Foo, Roger Sik Yin Heng, Chew Kiat Chan, Mark Yan Yee Cheung, Christine |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Tay, Kai Yi Wu, Kan Xing Chioh, Florence Wen Jing Autio, Matias Ilmari Pek, Nicole Min Qian Narmada, Balakrishnan Chakrapani Tan, Sock-Hwee Low, Adrian Fatt-Hoe Lian, Michelle Mulan Chew, Elaine Guo Yan Lau, Hwee Hui Kao, Shih Ling Teo, Adrian Kee Keong Foo, Jia Nee Foo, Roger Sik Yin Heng, Chew Kiat Chan, Mark Yan Yee Cheung, Christine |
| author_sort | Tay, Kai Yi |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:36:42Z |
| format | Journal Article |
| id | ntu-10356/165614 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:36:42Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1656142023-04-09T15:37:38Z Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease Tay, Kai Yi Wu, Kan Xing Chioh, Florence Wen Jing Autio, Matias Ilmari Pek, Nicole Min Qian Narmada, Balakrishnan Chakrapani Tan, Sock-Hwee Low, Adrian Fatt-Hoe Lian, Michelle Mulan Chew, Elaine Guo Yan Lau, Hwee Hui Kao, Shih Ling Teo, Adrian Kee Keong Foo, Jia Nee Foo, Roger Sik Yin Heng, Chew Kiat Chan, Mark Yan Yee Cheung, Christine Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Institute of Molecular and Cell Biology (IMCB), A*STAR Genome Institute of Singapore Science::Medicine Coronary Artery Disease Single Nucleotide Polymorphisms 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. Ministry of Education (MOE) Nanyang Technological University National Research Foundation (NRF) Published version The National Research Foundation, Singapore (Project Number 370062002) funded the Singapore Coronary Artery Disease Genetics Study (SCADGENS) and genotyping of the participants. The team from Nanyang Technological University Singapore was funded by an Academic Research Fund Tier 1 grant (2018-T1-001-030) from the Ministry of Education, Singapore, Human Frontier Science Program Research Grant (RGY0069/2019), and the Nanyang Assistant Professorship. K.Y. T. is supported by NTU Research Scholarship. H.H.L. is supported by the Institute of Molecular and Cell Biology (IMCB) Scientific Staff Development Award (SSDA) for her part-time Ph.D. A.K.K.T. is supported by IMCB, A*STAR, Precision Medicine and Personalised Therapeutics Joint Research Grant 2019, the 2nd A*STAR-AMED Joint Grant Call 192B9002 and NUHSRO/2021/035/NUSMed/04/NUS-IMCB Joint Lab/LOA. 2023-04-04T01:26:03Z 2023-04-04T01:26:03Z 2022 Journal Article Tay, K. Y., Wu, K. X., Chioh, F. W. J., Autio, M. I., Pek, N. M. Q., Narmada, B. C., Tan, S., Low, A. F., Lian, M. M., Chew, E. G. Y., Lau, H. H., Kao, S. L., Teo, A. K. K., Foo, J. N., Foo, R. S. Y., Heng, C. K., Chan, M. Y. Y. & Cheung, C. (2022). Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease. Atherosclerosis, 362, 11-22. https://dx.doi.org/10.1016/j.atherosclerosis.2022.10.012 0021-9150 https://hdl.handle.net/10356/165614 10.1016/j.atherosclerosis.2022.10.012 36435092 2-s2.0-85142361351 362 11 22 en 370062002 2018-T1-001-030 RGY0069/2019 Atherosclerosis © 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/). application/pdf |
| spellingShingle | Science::Medicine Coronary Artery Disease Single Nucleotide Polymorphisms Tay, Kai Yi Wu, Kan Xing Chioh, Florence Wen Jing Autio, Matias Ilmari Pek, Nicole Min Qian Narmada, Balakrishnan Chakrapani Tan, Sock-Hwee Low, Adrian Fatt-Hoe Lian, Michelle Mulan Chew, Elaine Guo Yan Lau, Hwee Hui Kao, Shih Ling Teo, Adrian Kee Keong Foo, Jia Nee Foo, Roger Sik Yin Heng, Chew Kiat Chan, Mark Yan Yee Cheung, Christine Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease |
| title | Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease |
| title_full | Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease |
| title_fullStr | Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease |
| title_full_unstemmed | Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease |
| title_short | Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease |
| title_sort | trans interaction of risk loci 6p24 1 and 10q11 21 is associated with endothelial damage in coronary artery disease |
| topic | Science::Medicine Coronary Artery Disease Single Nucleotide Polymorphisms |
| url | https://hdl.handle.net/10356/165614 |
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