ZNF827 pleiotropic cardiovascular risk locus involves regulation by nuclear factor-1

Area of Science:

• Genetics
• Cardiovascular Biology
• Molecular Biology

Background:

• Spontaneous Coronary Artery Dissection (SCAD) predominantly affects middle-aged women, causing myocardial infarction via intramural hematoma and heart ischemia.
• The ZNF827 locus on chromosome 4 is a known genetic risk factor for SCAD and other cardiovascular traits, but its molecular mechanisms remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms linking the ZNF827 locus to SCAD and related cardiovascular conditions.
• To identify the specific genetic variant and regulatory elements involved in SCAD risk associated with the ZNF827 locus.

Main Methods:

• Analysis of genetic associations and epigenetic markers.
• Reporter assays in vascular smooth muscle cells (SMCs) to assess variant effects on gene transcription.
• In silico prediction and experimental validation of transcription factor binding (NF1).
• Gene knockdown studies in human iPSC-derived SMCs and fibroblasts to evaluate ZNF827 function.

Main Results:

• The SCAD genetic risk locus colocalizes with a common intronic variant, rs13128814, overlapping with epigenetic markers in vascular cells.
• The SCAD-risk allele (rs13128814-A) increases transcriptional activity in SMCs, with evidence suggesting Nuclear Factor-1 (NF1) binding.
• ZNF827 knockdown in SMCs and fibroblasts dysregulated genes involved in macroautophagy and insulin signaling pathways.

Conclusions:

• The rs13128814 variant, potentially mediated by NF1, influences ZNF827 expression, providing a molecular basis for its association with SCAD and other cardiovascular risks.
• ZNF827 may function as a broad gene regulator in vascular SMCs and fibroblasts, contributing to arterial fragility in SCAD and related diseases.