The Chronic Renal Insufficiency Cohort (CRIC) study was established to identify important risk factors for the development of CVD in CKD and better understand the mechanisms of CVD in CKD. Dyslipidemia is commonly observed in patients with CKD and includes low levels of high density lipoprotein (HDL) cholesterol, elevation in certain forms of apolipoprotein (apo)- containing lipoproteins, and elevation in lipoprotein(a) [Lp(a)]. The results of these studies will inform both the issue of increased cardiovascular risk in CKD as well as the gene-environment interactions that influence the metabolism of HDL and apoB-lipoproteins in the milieu of CKD, additionally, they will definitively address for the first time the role of Lp(a) in influencing cardiovascular risk in CKD patients.

Public Health Relevance

Subjects with chronic kidney disease (CKD) are at substantially increased risk for cardiovascular disease (CVD), but the causes of this increased risk remain incompletely understood. The Chronic Renal Insufficiency Cohort (CRIC) study was established to identify important risk factors for the development of CVD in CKD and better understand the mechanisms of CVD in CKD. The University of Pennsylvania is the coordinating center for the CRIC study and the PI of this grant proposal, Dr Daniel Rader, is the director of the central laboratory and chair of the genetics subcommittee of the CRIC study. Dyslipidemia is commonly observed in patients with CKD and includes low levels of high density lipoprotein (HDL) cholesterol, elevation in certain forms of apolipoprotein (apo)-containing lipoproteins, and elevation in lipoprotein(a) [Lp(a)]. However, the mechanisms of the dyslipidemia of CKD, the genetic factors that operation within the mileau of CKD to promote dyslipidemia, and the relationship of specific aspects of the dyslipidemia, including genetic factors, to CVD, are poorly understood. The CRIC study provides an unparalleled opportunity to determine the role of genetic variation in influencing the lipid phenotype in the mileau of CKD and to determine in detail the relationship of dyslipidemia to CVD events in this population.
In Aim 1, we will test the hypothesis that common variation in a large number of candidate genes and pathways involved in the metabolism and function of HDL is associated with variation in plasma concentrations of HDL-C and associated apolipoproteins and predicts CVD events in CKD independent of HDL-C levels.
In Aim 2, we will test the hypothesis that common variation in a large number of candidate genes and pathways involved in the metabolism of apoB-containing lipoproteins is associated with variation in plasma concentrations of apoB-containing lipoproteins and predicts CVD events in CKD independent of LDL-C levels.
In Aim 3, we will test the hypothesis that plasma concentrations of Lp(a) increase as renal function decreases and that they predict CVD outcomes in patients with CKD. The results of these studies will inform both the issue of increased cardiovascular risk in CKD as well as the gene-environment interactions that influence the metabolism of HDL and apoB-lipoproteins in the mileau of CKS. In addition, they will definitively address for the first time the role of Lp(a) in influencing cardiovascular risk in CKD patients. The outcome is likely to provide novel approaches to predicting CVD risk in CKD and potentially new targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092209-02
Application #
7896807
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Liu, Lijuan
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$508,989
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104