The Dark Matter Project

Chromosome 9p21.3 - a risk locus for coronary artery disease

the most biomedically costly piece of genomic real estate

The goal of this project is to understand and reverse the effects of the most biomedically costly piece of genomic “real estate” - A risk haplotype for coronary artery disease (CAD) that resides in chromosome 9p21.3 and accounts for ~13% of CAD incidence in the US with an estimated healthcare burden of $30‐50 billion dollars per year in the US alone. This CAD risk haplotype is both highly prevalent (~50% allele frequency in most populations worldwide) and highly impactful (~40% increased risk for CAD per copy).

Approximately 100 variants lie in this region, overlapping a noncoding RNA called ANRIL (aka CDKN2A‐AS); yet we do not know which variant or variants are responsible for the increased CAD risk, and how. It is believed that this genomic region affects the vasculature, and in particular the vascular smooth muscle cells (VSMCs) (Lo Sardo V et al., Cell. 2018).

With collaboration with Kristin Baldwin’s lab at Columbia University, we are dissecting this locus by engineering human induced pluripotent cells (iPSCs) with different combinations of risk and non-risk haplotypes and analyzing their properties following differentiation to VSMCs. We hope to identify the causative variants and their underlying mechanism, which will potentially enable development of effective therapeutics targeting this locus.

IN COllaboration with:

Kristin Baldwin, Ph.D., Columbia University Irving Medical Center, Department of Genetics and Development