Title: Isoform-level transcriptional program of smooth muscle cells in coronary artery disease
Abstract: Coronary artery disease (CAD) remains a leading cause of death worldwide, and is characterized by the buildup of plaques in the coronary arteries. Approximately 300 genomic loci have been linked to CAD susceptibility. Of these, the 9p21.3 locus is the most impactful, but its location in a noncoding area of the genome has made it difficult to study, and the mechanism by which it causes risk is still unclear. To investigate how this region contributes to disease and how it affects cells of the vasculature, we use induced pluripotent stem cell (iPSC) derived vascular smooth muscle cells (VSMC) that are genetically engineered to carry the risk or non-risk version of this locus. We use VSMCs because they comprise the majority of the arterial wall and contribute significantly to plaque buildup and vessel stiffening during CAD. By using iPSC-VSMCs, we uncover that the 9p21.3 region alters RNA splicing of hundreds of transcripts. Moreover, we found that about 200 genes across the transcriptomes have significant differential isoform usage. Overall, this work demonstrates that the 9p21.3 risk locus has a broad impact on RNA processing and smooth muscle cell phenotype, providing new insight into how genetic variation at this locus may drive vascular disease.
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