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SCAD genetic risk loci, such as the ZNF827 locus on chromosome 4, were previously associated with the risk for coronary artery disease, systolic blood pressure, and ascending aortic diameter variability, but the molecular processes driving these genetic associations are unknown. In the present study, we demonstrated that these genetic associations were colocalized and could all be explained by the intronic common variant rs13128814, which overlapped epigenetic regulatory markers specifically active in vascular smooth muscle cells (SMCs) and fibroblasts. Using reporter assay experiments, we found that the SCAD-risk allele (rs13128814-A) was associated with increased transcriptional activity in A7r5 SMCs. In silico predictions and reporter assays suggested nuclear factor-1 (NF1) transcription factors to preferentially bind to SCAD risk allele. We found that SCAD genetic association colocalized with a ZNF827 eQTL association in artery tissues. Knockdown of ZNF827 in human iPSC-derived SMCs and fibroblasts identified a large number of dysregulated genes enriched in relevant pathways such as macroautophagy and insulin signaling. Our findings support the NF1-dependent rs13128814 effect on the expression of ZNF827 as a potential molecular mechanism underpinning multiple cardiovascular trait genetic risk loci. ZNF827 may act as a broad regulator of gene expression in vascular SMCs and fibroblasts. Further investigation using multiple cell types, organoids, and in vivo models may clarify the implications of ZNF827 in arterial fragility observed in SCAD and other arterial diseases.<\/jats:p>","DOI":"10.1042\/cs20257956","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T13:38:36Z","timestamp":1776260316000},"page":"791-804","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>ZNF827<\/i>\n                    pleiotropic cardiovascular risk locus involves regulation by nuclear factor-1"],"prefix":"10.1042","volume":"140","author":[{"given":"Yingwei","family":"Liu","sequence":"first","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"},{"name":"2Stanford Cardiovascular Institute, Stanford University School of Medicine, CA, U.S.A."},{"name":"3Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, CA, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asraa","family":"Esmael","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Tezza","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"London","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaux-Alison","family":"Fustier","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Georges","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5424-2134","authenticated-orcid":false,"given":"Nabila","family":"Bouatia-Naji","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"2026050504163646900_B1","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1016\/j.jacc.2020.05.084","article-title":"Spontaneous coronary artery dissection: JACC state-of-the-art review","volume":"76","author":"Hayes","year":"2020","journal-title":"J. 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