DISCOVERY AND VALIDATION OF NOVEL LOCI ASSOCIATED WITH HDL FUNCTION
Saleheen Danish
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 1R01HL111398-01 from National Heart, Lung, And Blood Institute
Abstract: 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
Keywords: aryldialkylphosphatase; Atherosclerosis; base; Biological; Biological Assay; Biology; biomarker; Cardiovascular Diseases; cardiovascular disorder risk; cardiovascular risk factor; Cardiovascular system; Cells; Cholesterol; Clinical; Clinical Medicine; cohort; Collaborations; Computer Simulation; Coronary Arteriosclerosis; cost effective; Data; Data Set; Etiology; European; follow-up; Funding; Genes; Genetic; Genetic Determinism; genetic epidemiology; genetic manipulation; genome wide association study; genome-wide; Genotype; Health Professional; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Housing; in vivo; International; Ischemic Stroke; Joints; Lipids; macrophage; Measurement; Measures; Metabolic; mouse model; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; novel; Nurses` Health Study; Outcome; Pakistan; Participant; Pathway interactions; Phenotype; Plasma; Population; Property; Publishing; reverse cholesterol transport; Risk; skills; South Asian; Staging; Translating; Validation
Relevance: 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
Project start date: 2012-01-01
Project end date: 2016-11-30
Budget start date: 1-JAN-2012
Budget end date: 30-NOV-2012
1R01HL111398-01 (2012): $679450
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