The overall aim of the proposed research is to investigate the molecular basis of an isolated low level of high density lipoprotein cholesterol (HDL-C). Despite the well-established association between low HDL-C and coronary artery disease (CAD), a systematic investigation of the genetic basis for this disorder has not been undertaken. To explore the molecular basis and associated cellular mechanisms underlying isolated low HDL-C, severely affected subjects and biologic family members have been identified throughout the United States.
The specific aims of the proposed research include: 1.) Identify protein abnormalities in subjects with isolated low HDL-C. The hypothesis to be tested is that alterations in structural (apolipoprotein AI) or functional (LCAT) proteins are responsible for isolated low HDL-C. 2.) Identify novel mutations in the apolipoprotein AI and LCAT gene. The hypothesis to be tested is that mutations in the apo AI gene alters high affinity binding and cholesterol efflux in cultured fibroblasts and mutations in the LCAT gene alter expression of enzymatic activity. 3.) Determine whether novel mutations or specific genetic markers segregate with low HDL-C and/or premature CAD. The hypothesis to be tested is whether polymorphic DNA microsatellite regions are informative in families with isolated low HDL-C. The collection of subjects with the most extreme forms of this disorder provides the ideal population to address this fundamental question. These systematic studies should elucidate the significance of isolated low HDL-C as a risk factor for CAD and serve as prerequisite for future development of therapeutic strategies in the management of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL052663-04
Application #
2702254
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1995-05-01
Project End
1999-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201