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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111398-02
Application #
8403772
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Liu, Lijuan
Project Start
2012-01-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$645,352
Indirect Cost
$242,007
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104