Dissecting cardiovascular disease-associated noncoding genetic variants using human iPSC models.

Advancements in genomics have revealed hundreds of loci associated with cardiovascular diseases, highlighting the role genetic variants play in disease pathogenesis. Notably, most variants lie within noncoding genomic regions that modulate transcription factor binding, chromatin accessibility, and thereby the expression levels and cell type specificity of gene transcripts. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a powerful tool to delineate the pathogenicity of such variants and elucidate the underlying transcriptional mechanisms. Our review discusses the basics of noncoding variant-mediated pathogenesis, the methodologies utilized, and how hiPSC-based heart models can be leveraged to dissect the mechanisms of noncoding variants.