Abstract 720: Integration Of Population Genetic And Human Knockout Studies With Smooth Muscle Cell Lineage Tracing In Mouse Models Identifies Novel Targets For Atherosclerosis And Cardiovascular Risk.

Abstract

Despite lipid-lowering therapies, residual cardiovascular disease risk remains a major unmet clinical need. Large-scale genetic analyses have identified >250 loci for coronary artery disease (CAD) risk. Genes that function in vascular smooth muscle cells (SMC) are causal at several loci, yet the causal genes at most loci remain unknown. Using single cell profiling and SMC lineage tracing in mouse models, we and others have shown that SMC transition through an intermediate state to SMC-derived cells (SDC) with protective or harmful phenotypes for plaque stability. In this study, we integrated SMC lineage tracing in mouse models with ongoing analyses in > 1 million human participants with whole-genome (WGS) and whole-exome sequencing (WES) data, as well as rare variant analysis of human “knockouts” (homozygous for predicted loss-of-function variants) for a novel gene discovery pipeline (Figure 1). Through WES in 76,000 highly consanguineous participants in the Pakistan Genomic Resource (PGR), we assembled the largest global cohort of human KOs. At non-lipid CAD loci from a recent large multi-ethnic meta-analysis (~1.1 million participants), we prioritized genes as potentially causal in SMC/SDC as those that are expressed and regulated in human or mouse arteries and SMC in atherosclerosis progression. Through gene burden testing and analyses of rare predicted loss-of-function (pLoF) and damaging (pDMs) variants in the largest CAD WES/WGS meta-analyses we enriched for causal genes. We restricted to genes with at least 5 pLoF carriers in PGR to facilitate recall studies in Pakistan. Final prioritization incorporated state-of-the-art fine mapping and co-localization analyses as well as biological plausibility. From an initial pool of 1696 genes, our gene discovery pipeline prioritized 15 SMC/SDC genes, and initial recall in PGR identified multiple large pedigrees for mutations in candidate causal genes PDE3A, SERPINH1, HHIPL1, and ZEB2.