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Setting the Stage for Personalized Medicine
New Association Identified between Statin Efficacy and Single Nucleotide Polymorphisms in the HMGCR Gene

"Investigating differences like these is what could lead to a better under-standing of some of the mechanisms that modify statin efficacy - and that could ultimately lead to greater clinical benefit for many people."

In a new study published in Circulation, CHORI senior scientist Ronald Krauss, MD, and his colleagues identified a novel gene variation that provides one more piece of the puzzle in developing personalized medicine. Using genomic sequencing on the gene that codes for hydroxymethyl glutaryl coenzyme A reductase (HMGCR), the enzyme targeted by statins, Dr. Krauss hoped to find clues as to how to make that group of cholesterol-lowering drugs more effective.

“In the current study we found a series of single neucleotide polymorphisms, or SNPs in the HMGCR gene that collectively resulted in a lower statin response,” says Dr. Krauss.

While statins have had a revolutionary impact on current cholesterol management, two-thirds of individuals on treatment remain at high risk for cardiovascular disease, leaving significant room for improvement.

"A 30 percent reduction in risk is quite an important effect on the health of this country, but our goal is to try to understand how we might improve treatment even more by identifying the factors that lead to greater improvement in risk in some populations, but not in others," Dr. Krauss explains.

Statins work by blocking the action of HMGCR, the most critical enzyme involved in the pathway for cholesterol production in the body, making the HMGCR gene a natural target for genomic studies geared at better understanding what genetic influences might be at play in determining the efficacy of statin response.

"What we found was a small but significant difference between African Americans and Caucasians in the amount of cholesterol lowering that was achieved, which corresponded with a series of SNPs also found only in a small subset of African Americans that could collectively account for that lowered statin response," Dr. Krauss explains.

While the difference is not large enough to suggest that African Americans as a whole won't benefit from statin treatment, it does provide evidence that genes can significantly impact on statin efficacy. When more such effects are identified and harnessed, the era of personalized medicine, in which patients can be treated with different kinds or doses of drugs based on their genetic differences, will move into high gear.

In addition, Dr. Krauss also found that the very same SNPs that were associated with a lowered statin response were responsible for a lowered level of low density lipoproteins (LDLs), or bad cholesterol as well - but under normal baseline conditions and before treatment with statins.
"This result is of particular interest as we already know that lowering LDL levels is beneficial for heart disease prevention. This genetic condition would basically confer lifelong reduction in LDL.
As Dr. Krauss points out, "That's a way of preventing disease at the very outset, which has a much more dramatic and beneficial effect than trying to lower cholesterol later in life."

Rather than presenting a problem, these SNPs which result in a reduced response to statins may actually represent a protective benefit. It's just this kind of information Dr. Krauss was looking for, as further down the road such clues could very well provide the key to cholesterol treatment and prevention.

"It's primary value is to set the stage for future studies that could expand our repertoire of genetic variation to include a much more comprehensive look at all the genes," says Dr. Krauss. "It's the first step in a process that is leading toward personalized medicine - in which we can use genetics and other information about individuals to help design the most appropriate treatments for disease prevention."

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Tuesday, May 17, 2011 8:19 AM

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