Gene Variation May Block Cholesterol Drugs

Ivanhoe Newswire
Friday, June 20, 2008; 4:15 AM

(Ivanhoe Newswire) – A gene variation may be why cholesterol-lowering drugs don't work in some people.

The gene variation, called alternative splicing, explained nine-percent of the drugs' decreased power to reduce the bad cholesterol or low-density lipoprotein (LDL). The study is the first to show that a change in a biological process contributes substantially to the effectiveness of cholesterol-lowering drugs known as statins. Statins work by blocking a key enzyme required for the production for cholesterol called HMGCR.
 
"Nine percent is a large number," senior author, Ronald Krauss, M.D., Children's Hospital Oakland Research Institute in California, was quoted as saying. "When we look at individual variations in genes affecting cholesterol metabolism, we can usually explain only a few percent of the variability in statin response."

Researchers analyzed differences in how the gene responsible for producing HMGCR was processed, or spliced, in 900 people. During splicing some parts of the gene's first product, mRNA, are removed and others are combined. The enzyme that is produced from the normally spliced HMGCR mRNA is critical to the body's production of cholesterol. Statins can block its activity. But the other spliced form is more resistant to statin inhibition of cholesterol production.

The discovery of this gene variation could lead to better ways to treat cholesterol and new treatments for other chronic diseases. Understanding alternative splicing can have other benefits, including a better understanding of cholesterol metabolism.

SOURCE: Circulation: Journal of the American Heart Association, published online June 16, 2008

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