Gene points to HDL drug target

Cardiovascular disease Blocking enzyme raises HDL levels.

New cholesterol drugs could be developed following the discovery of a rare gene mutation which raises high-density lipoprotein (HDL) levels.

Studies in animals have suggested that lower levels of the endothelial lipase enzyme are associated with raised HDL levels. Increased HDL levels are, in turn, linked to protection from atherosclerotic cardiovascular disease.

Researchers from the University of Pennsylvania examined the gene coding for endothelial lipase in humans to see whether mutations were associated with changes in HDL levels.

The researchers sequenced this gene in 585 individuals, 372 of whom had high HDL levels and 213 of whom had low HDL levels. They found seven mutations that only occurred in individuals with high HDL levels.

Computer modelling suggested that most of these mutations impaired the function of the enzyme and would therefore lead to elevated HDL levels.

A drug which blocked the function of endothelial lipase would therefore be likely to raise HDL levels, the researchers point out.

In addition, linking genetic data to activity of an enzyme and to outcomes provides 'powerful validation' of the appropriateness of developing cholesterol treatments aimed at inhibiting endothelial lipase, they argue.

Inhibiting this enzyme may not have health consequences since people with low levels of the enzyme, and raised HDL levels, appear to be healthy.

Such a targeted approach to the development of drugs aimed at raising HDL levels would bring considerable benefits, the researchers say.

'Pharmacological options to raise HDL cholesterol concentration are currently limited,' they point out.

'The increasing costs of developing and testing new drugs, particularly when so many fail human trials even after exten-sive testing in animal models, necessitates prioritisation of targets that are most likely to produce safe and effective drugs.'

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