Plasma levels of HDL-C are inversely associated with the risk of atherosclerotic cardiovascular disease (CVD). However, the causal basis of this association has been questioned and there is a need for further studies on HDL functionality and its relationship to CVD. HDL """"""""cholesterol efflux capacity,"""""""" a prototypical measure of HDL function, is significantly associated with atherosclerotic CVD - however, the factors that influence HDL cholesterol efflux capacity are poorly understood. South Asians are particularly well-suited to investigate biological determinants of novel cardiovascular risk factors and their genetic determinants because of the high burden of cardio-metabolic conditions in these populations. Our existing collaborative framework of studies in South Asians provides a unique opportunity to conduct powerful studies to investigate genes related to HDL function. We hypothesize that the combination of a robust assay for HDL function, considerable statistical power, and involvement of a population that has particularly high rates of CVD will enhance ability to discover genetic determinants of a key HDL function, namely cholesterol efflux capacity. We will employ a GWAS approach to discover genetic loci associated with HDL cholesterol efflux capacity in South Asians and replicate in both South Asians and Europeans. We will evaluate loci found to be significantly associated with cholesterol efflux capacity for their association with cardiovascular outcomes (MI, ischemic stroke) in South Asians and Europeans. Finally, we will perform functional validation of at least one novel locus significantly associated with cholesterol efflux capacity. These studies will advance understanding of the pathways that modulate HDL function and help to prioritize translational strategies that will ultimately reduce the risk of cardiovascular diseases.
We will perform assays related to HDL function (cholesterol efflux capacity and paraoxonase) in the Pakistan Risk of Myocardial Infarction Study (PROMIS). We will utilize existing genome wide association data to identify loci associated with the phenotypes perform replication studies in additional South Asian and European populations and determine the relationship with coronary artery disease in larger populations. We will further explore the mechanism using mouse models.
|Khetarpal, Sumeet A; Babb, Paul L; Zhao, Wei et al. (2018) Multiplexed Targeted Resequencing Identifies Coding and Regulatory Variation Underlying Phenotypic Extremes of High-Density Lipoprotein Cholesterol in Humans. Circ Genom Precis Med 11:e002070|
|Tall, Alan R; Rader, Daniel J (2018) Trials and Tribulations of CETP Inhibitors. Circ Res 122:106-112|
|Koekemoer, Andrea L; Codd, Veryan; Masca, Nicholas G D et al. (2017) Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity. Arterioscler Thromb Vasc Biol 37:1956-1962|
|Khera, Amit V; Demler, Olga V; Adelman, Steven J et al. (2017) Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 135:2494-2504|
|Kuwano, Takashi; Bi, Xin; Cipollari, Eleonora et al. (2017) Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport. J Lipid Res 58:731-741|
|Cuchel, Marina; Raper, Anna C; Conlon, Donna M et al. (2017) A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans. J Lipid Res 58:752-762|
|Javaheri, Ali; Molina, Maria; Zamani, Payman et al. (2016) Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients. J Heart Lung Transplant 35:1295-1302|
|Zanoni, Paolo; Khetarpal, Sumeet A; Larach, Daniel B et al. (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351:1166-71|
|Khetarpal, Sumeet A; Schjoldager, Katrine T; Christoffersen, Christina et al. (2016) Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents. Cell Metab 24:234-45|
|Hsieh, Joanne; Koseki, Masahiro; Molusky, Matthew M et al. (2016) TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis. Nature 535:303-7|
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