ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

Abstract

AbstractIntroductionSCAD (spontaneous coronary artery dissection) is a form of myocardial infarction that disproportionately affects young women. SCAD is caused by the formation of a hematoma within coronary artery wall, resulting in its blockage. Sixteen SCAD susceptibility loci are currently known, includingZNF827gene locus on chromosome 4. Several common genetic variations withinZNF827are also linked to coronary artery disease (CAD), systolic blood pressure (SBP), and ascending aortic diameter. The molecular processes driving these genetic connections, however, are unknown.MethodsWe performed fine-mapping and genetic colocalization analysis atZNF827locus on multiple GWAS signals and quantitative expression traits. We explored the regulatory function of sequences of interest using a luciferase reporter system in rat smooth muscle cells. We used siRNA to knockdown the expression of gene and assessed transcriptomic changes through bulk RNA-Seq.ResultsThe genetic association signals for SCAD, CAD, blood pressure, and aorta dimensions could all be explained by a single causal variant. We identified rs13128814 as the most likely causative variant. This variant overlaps epigenetic regulatory markers specifically active in vascular SMCs and fibroblasts. A 1kb region containing the SCAD-risk allele (A) of rs13128814 variant had a transcriptional activation impact, while the protective allele (G) had no effect.In silicopredictions found nuclear factor 1 (NF1) transcription factors preferentially bind to the A allele of rs13128814. We found that overexpressing NFIA (Nuclear Factor 1 A-Type) activated transcription in this area. SCAD association andZNF827eQTL colocalization in various vascular tissues suggested the latter as a plausible target gene in this locus. Knockdown of ZNF827 in iPSC-derived SMCs and fibroblasts, followed by RNA-seq, identified a large number of dysregulated genes, including multiple genes involved in cardiovascular disease.ConclusionOur findings inZNF827locus support the hypothesis that the rs13128814 variant, which may affect the binding of NF1 family transcription factors and causeZNF827expression to be deregulated, is the molecular mechanism underpinning the relationship of theZNF827locus with numerous cardiovascular disorders.ZNF827acts as a regulator of gene expression in vascular SMCs and fibroblasts. Further investigation ofZNF827function in vascular tissue will be required to understand the implications of its dysregulation on cardiovascular physiopathology.