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Genetics of HDL regulation in humans
Michael Miller1, Jeffrey Rhyne, Steven Hamlette
1Departments of Medicine and Epidemiology, Veterans Affairs and University of Maryland Medical Center, Baltimore, MD 21201, USA. mmiller@heart.umaryland.edu
Insights
Gene regulation of high-density lipoprotein cholesterol (HDL-C) is key to understanding vascular disease. Targeting genes like ABCA1 and APOA1 offers new therapeutic avenues for reducing cardiovascular events.
Area of Science:
- Genetics and Molecular Biology
- Cardiovascular Disease Research
- Metabolic Disorders
Background:
- High-density lipoprotein cholesterol (HDL-C) inversely correlates with vascular and coronary heart disease.
- The identification of ABCA1's role in reverse cholesterol transport significantly advanced HDL gene regulation research.
Purpose of the Study:
- To review the gene regulation of HDL-cholesterol.
- To discuss molecular abnormalities in HDL candidate genes linked to human pathologies.
Main Methods:
- Review of existing literature on HDL gene regulation.
- Analysis of molecular abnormalities in candidate HDL genes.
- Discussion of therapeutic targets for modulating HDL levels.
Main Results:
- ABCA1 is pivotal in reverse cholesterol transport.
- Potential targets for increasing HDL include upregulators of ABCA1 and APOA1 (e.g., PPAR and LXR agonists) and CETP downregulators (e.g., JTT-705).
- Other nuclear receptors are under investigation in animal models.
Conclusions:
- Monogenic disorders of HDL metabolism do not always correlate with premature vascular disease.
- Understanding genetic factors in HDL and reverse cholesterol transport offers opportunities for novel therapies.
- Optimizing HDL function may reduce vascular event rates beyond current LDL-lowering strategies.
Purpose Of Review:
To review gene regulation of HDL-cholesterol and discuss molecular abnormalities in HDL candidate genes that may lead to human pathologic states.
Recent Findings:
The inverse association between HDL-cholesterol and vascular disease, especially coronary heart disease, has long been recognized, but understanding gene regulation of HDL in humans gained considerable momentum following the identification of ABCA1 as playing a pivotal role in reverse cholesterol transport. Recent data suggest that potentially important targets for upregulating HDL in humans include upregulators of ABCA1 and APOA1 (e.g. peroxisome proliferator activated receptor and liver X receptor agonists) and downregulators of CETP (e.g. JTT-705). A host of other nuclear receptors under investigation in animal models may advance to human testing in the near future.
Summary:
Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.