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Principal Investigator: Muredach P Reilly
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $647,099
Funding agency: National Heart Lung and Blood Institute
Despite effective LDL-C therapies, cardiovascular disease (CVD) risk remains a major unmet clinical need. We
and others have identified >300 loci for coronary artery disease (CAD). 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 found that SMC transition through an intermediate
SMC-derived cell (SDC) state into protective or harmful phenotypes that modulate disease. We hypothesize that
SMC genes play a prominent causal role in plaque instability and CVD risk independent of lipoprotein genes. To
address this, we will leverage unique mouse model and human resources, including the Pakistan Genomics
Resource (PGR, n=250,000 for study) that includes the largest global cohort of human gene knockout “KOs”
(complete KOs >5000; heterozygous KOs >18,000 genes) as well as the Munich Vascular Biobank (MVB) with
>2,000 human plaques and clinical, histology, transcriptomics and genetic data. In Aim 1, we will integrate SMC
lineage tracing in mouse models with analyses of >1 million participants with GWAS SNP, whole-exome (WES)
and whole-genome (WGS) data, eliminating all loci/genes associated with plasma lipoproteins. Implementing
the largest rare variant and gene burden testing for CAD to date, we will prioritize likely causal SMC/SDC genes
and reveal predicted loss of function (pLoF) variant directional effects. To operationalize call-back studies, we
will limit to genes with at least 5 pLoF carriers in PGR. Gene priority will be refined by multiethnic fine-mapping,
co-localization analyses and biological plausibility. We expect to prioritize ~30 SMC/SDC genes. All will undergo
large PheWAS for pleiotropy and safety. For the top 5 genes, call-back studies will validate causality and
directionality and assess safety through deep phenotyping of atherosclerosis traits, safety and pleiotropy markers
in PGR families (n=200 per family). Preliminary work prioritized 15 SMC/SDC genes, all strong causal
candidates, and initial call-back in PGR expanded large pedigrees for the most promising genes (e.g., PDE3A,
SERPINH1, HHIPL1, ZEB2). In Aim 2, we will use RNA in situ sequencing (HybRISS), RNA-scope, proximity
ligation assays (Myh11-H3K4me2 SMC/SDC mark) and histology to define SMC/SDC gene expression and
location for ~30 prioritized genes in stable vs. unstable MVB plaques. Change in allele specific expression for
genes in SDC types in stable vs. unstable MVB plaques and co-localization of their cis-eQTLs to CAD SNPs will
inform causal and directional effects on plaque stability. For at least 2 top genes, we will use a Tet-on Dre/Cre
dual inducible recombinase system for SMC gene deletion at late time points to test effects and mechanisms on
features of plaque stability in advanced lesions and disease regression. We are poised to test in mouse models
if PDE3A, one compelling example, promotes SMC proliferation, senescence and vascular remodeling. Overall,
we propose a unique integrative platform, validated by human genetics, to fine-map loci, discover causal genes
and elucidate safe therapeutic targets in SMC/SDCs causal pathways for atherosclerosis stability and CVD risk.
Terms: <ATRA><Acceleration><Address><Affect><Alleles><Allelomorphs><Arterial Fatty Streak><Arterial Fatty Streaks><Arteries><Assay><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Bioassay><Biological><Biological Assay><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Vessels><Callback><Cardiovascular Diseases><Carotid Arteries><Carotid Artery Plaque><Carotid Artery Plaques><Causality><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Lineage><Cell Multiplication><Cell Proliferation><Cell Senescence><Cell Signaling><Cells><Cellular Aging><Cellular Proliferation><Cellular Senescence><Cholesterol><Clinical><Closure by Ligation><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Data><Disease><Disease regression><Disorder><Etiology><Family><GWA study><GWAS><Gene Deletion><Gene Expression><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Variation><Genetic analyses><Genetic defect><Genome Mappings><Heterozygote><Histology><Human><Human Genetics><Human Resources><Intracellular Communication and Signaling><Knock-out><Knockout><LDL><LDL Lipoproteins><Leiomyocyte><Lesion><Ligation><Lipids><Lipoproteins><Location><Low-Density Lipoproteins><Manpower><Maps><Meta-Analysis><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><Non-Polyadenylated RNA><Pakistan><Participant><Pathway interactions><Pedigree><Phenotype><Plasma><Plasma Serum><Play><Population Genetics><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Replicative Senescence><Research Resources><Residual><Residual state><Resolution><Resources><Reticuloendothelial System, Serum, Plasma><Retinoic Acid><Ribonucleic Acid><Role><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Stable Disease><System><Testing><Time><Trans Vitamin A Acid><Tretinoin><Tretinoinum><Variant><Variation><Vascular Smooth Muscle><Vascular remodeling><Vitamin A Acid><Work><all-trans-Retinoic Acid><all-trans-Vitamin A acid><atheromatosis><atherosclerosis plaque><atherosclerotic coronary disease><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><beta-Lipoproteins><biobank><biologic><biological signal transduction><biorepository><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><carotid plaque><causal allele><causal gene><causal mutation><causal variant><causation><causative mutation><causative variant><cell type><cohort><conditional knock-out><conditional knockout><coronary arterial disease><coronary artery calcium><coronary calcium><disease causation><entire genome><exome><exomes><fine art><full genome><gene deletion mutation><gene function><genetic analysis><genetic pedigree><genome mutation><genome resource><genome sequencing><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic data resource><genomic resource><genomic sequencing resource><heterozygosity><human model><improved><in situ sequencing><intima medial thickening><intima-media thickness><intimal medial thickening><knockout gene><loss of function><model of human><mouse model><multi-ethnic><multiethnic><murine model><pathway><pedigree structure><personnel><pleiotropic effect><pleiotropism><pleiotropy><programs><rare allele><rare mutation><rare variant><recombinase><resolutions><safety assessment><senescence><senescent><social role><therapeutic target><trait><trans-Retinoic Acid><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><transcriptomics><vascular><vulnerable plaque><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>