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Title: Gene Variation Explains Ineffectiveness of Cholesterol-Lowering Drugs in Some Patients
URL: http://www.pslgroup.com/dg/223CA6.htm
Doctor's Guide
June 18, 2008

DALLAS -- June 18, 2008 -- A variation in the way the body processes a single protein may explain why some people don't respond well to drugs that lower low-density lipoproteins (LDL), according to a report in Circulation: Journal of the American Heart Association.

The gene variation, called alternative splicing, explained 9% of statins' decreased power to reduce LDL in study participants compared with people with the standard processing pathway. The study is the first to show that a change in a biological process contributes substantially to the effectiveness of statins.

"Nine percent is a large number," said senior author of the study Ronald Krauss, MD, Children's Hospital Oakland Research Institute, Oakland, California. "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."

Dr. Krauss and his team sought a genetic explanation for this variability. They analysed differences in how the gene responsible for producing the cholesterol enzyme, called HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), was spliced among more than 900 participants enrolled in the Cholesterol and Pharmacogenetics (CAP) Study. The enzyme that is produced from the normally spliced HMGCR messenger ribonucleic acid plays an early and critical role in the body's production of cholesterol, and its activity can be strongly inhibited by statins. The alternatively spliced form, on the other hand, is more resistant to statin inhibition of cholesterol production.

Researchers found that the alternative splicing also accounted for 15% of the reduced response of apolipoprotein B (apoB) to simvastatin and 6% of the lower triglyceride response to the drug.

Combining factors already known to affect statin response with alternative splicing explains 24% of the variation in LDL response, 29% for apoB, and 8% for triglycerides, Dr. Krauss said. Despite this variability, statins are generally highly effective for prevention and treatment of heart disease, and there is not yet sufficient evidence for using genetic testing in evaluating the degree of benefit that individuals might be expected to achieve from statin treatment.

"The implications could go well beyond the efficacy of statins by helping us to understand the differences among individuals in how cholesterol is metabolised," Dr. Krauss said.


SOURCE: American Heart Association

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