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Ushering in the Era of Personalized Medicine
CHORI Researchers Discover Alternative mRNA Splicing Impacts Statin Efficacy

"We're trying to understand the basis for individual variability using genetic information, which may lead to new treatment approaches or new tools for making statins more effective or for reducing heart disease risk."

In the latest results published from the NIH-funded Cholesterol and Pharmacogenics (CAP) study, CHORI scientists Ronald Krauss, MD and Marisa Wong Medina, PhD report in Circulation’s June issue first-time evidence that a biological process is significantly associated with variation in statin response. As Dr. Krauss and his colleagues report, HMGCR, the protein which statins target in order to reduce LDL or “bad” cholesterol, undergoes alternative mRNA splicing, producing a slightly modified protein, or isoform, associated with variation in statin efficacy.

“We’ve identified in this study an important relationship between the amount of spliced isoform that an individual produces in their cells, and statin efficacy, such that variation in the amount of splicing was very strongly related to the magnitude of statin effect,” says Dr. Krauss.

While statins have revolutionized cholesterol treatment in the last decade, individuals have a widely varied response to the drugs, with some people experiencing no reduction in LDL while others' LDL can be reduced by as much as two-thirds. As a result, researchers have been teasing out possible explanations for this variation. Factors such as age, smoking, weight, and environmental impacts are a part of it, but so is a person's individual genetic make-up.

The latest piece of the puzzle Drs. Medina and Krauss have identified is the impact that alternative mRNA splicing can have on drug efficacy: Dr. Krauss and his colleagues found that up-regulation of the alternative HMGCR isoform was correlated with smaller reductions in overall cholesterol, LDL cholesterol, and apoprotein B and triglycerides. In addition, the HMGCR isoform was correlated with 6 to 15 percent of the variation in statin response.

"Ideally we'd like to be able to explain 100 percent of the variation, but one can't possibly expect that from just a single component, when we already know statin response is influenced by many different factors. That said, for one factor alone to contribute nearly 10 percent to the variation is incredibly high, higher than any other contributing factor yet found," Dr. Krauss says.

While the Circulation publication is significant in its identification of such a highly influential factor on statin variation, Dr. Krauss' study has even larger implications on the nature of genome research and the ultimate goal of personalized medicine.
"There's a general issue that we've tapped into here, and that is that the genome in humans consists of roughly 30 thousand genes but there are many more proteins the body makes, and many more variations of those proteins due to alternative splicing."
"As we move into the area of personalized medicine and have more and more information available to us about an individual's DNA, we're going to have to realize that this alone is a small piece of the genetic story," Dr. Krauss continues.

"Understanding how genetic variability relates not just to differences in genes, but to differences in the way those genes are processed, is essential to applying this information in any clinical way."

With continued research and development the likes of Dr. Krauss and his colleagues, that era of personalized medicine in which treatments can be optimized for different individuals based on their specific characteristics, genetic and otherwise, may not be as far off as one might think. Nevertheless, Dr. Krauss is quick to point out the many resources for heart disease risk already available in the mean time.

"In addition to statins, which work well for a great number of people, there is still a considerable amount of benefit that everyone in the population can achieve simply by following the recommendations we already have for a healthy lifestyle, healthy diet, and forphysical activity," says Dr. Krauss.
"If those recommendations are followed and we could prevent obesity and its complications before it starts, we'd have much less need for these medications and optimizations in the first place."


Tuesday, May 17, 2011 8:19 AM

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