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Finding New and Better Treatments
CHORI Scientist Garners 13 Million Dollar NIH Grant
The National Institutes of Health (NIH) Pharmacogenetics Research Network (PGRN) has announced that CHORI senior scientist Ronald Krauss, MD, will receive an award of $13.23 million for a five-year renewal of his grant, Pharmacogenomics and Risk of Cardiovascular Disease (PARC). Active since 2001 and already renewed once, the PARC grant focuses on identifying the genetic basis for the wide variation in effectiveness of statin treatment for reducing the risk of coronary heart disease.

"Heart disease is the leading cause of death in the United States, and largely due to changes in lifestyle, it is on the rise around the world, making it likely to become the leading cause of death worldwide in the next few years," says Dr. Krauss.
“The effective treatment of heart disease has a huge impact on global health and economics.”


Statins are a family of drugs that have been shown to lower cholesterol and reduce heart disease risk. They have shown a consistent reduction in heart disease in various populations of 30 to 40 percent, and are among the largest selling class of drugs in the world.

"That is a very important reduction in risk," says Dr. Krauss, "but it still leaves up to 70 percent or more individuals who are taking statins at risk for heart disease. We think a substantial portion of that variation can be attributed to genetics."

As a result, investigating the genetic basis for variation in statin response makes a fitting avenue of study for the NIH PGRN program, which was established in 2000 to determine how genetic information can be utilized to maximize the benefits and minimize the risk of individual drugs across a variety of diseases and research fields.
“Pharmaco-
genomics has really been the promise of personalized medicine for many years, and is aimed at trying to understand the genetic basis for individual differences in the way that drugs act.”
NIH Director Francis S. Collins, MD, PhD, says that thanks to breakthroughs in genome sequencing technologies and a growing understanding of genetic variation among individuals, there has never been a better time to propel the field of pharmacogenomics.

"Through these studies, we are moving closer to the goal of using genetic information to help prescribe the safest, most effective medicine for each patient," says Dr. Collins.

Dr. Krauss's PARC program fits into the PGRN by undertaking a series of interlinking aims that provide a powerful means of both identifying and understanding the genetic effects behind variation in statin response. Composed of an interdisciplinary consortium of expert researchers from different institutions with critical expertise in genomics, statistics, informational genetics and cardiovascular clinical practice, the PARC group will utilize a variety of genomic tools to achieve its aims. Dr. Krauss and his colleagues will use genome-wide association studies (GWAs) to scan the human
genome for variations (called single nucleotide polymorphisms or SNPs) that are associated with statin-induced reductions in the main target of statin drugs, low-density lipoproteins (LDL). Because GWAs may not capture all important genetic variation, complementary genomic approaches, including studies in cellular models, will be integrated with the GWA findings to identify genes that modulate statin responsiveness. Further detailed analyses of these genes will be carried out to determine their functions and to identify those SNPs that are most strongly associated with statin's effects.

"We will then test the ability of these SNPs to predict heart disease outcomes in diverse patient groups receiving statin treatment," explains Dr. Krauss. "This is really the reason d'ętre of the whole program."

Dr. Krauss points out that development of a genetic test for determining whether a given individual would benefit from statin treatment will require more extensive clinical studies. However, the PARC grant is also structured to provide information that could lead to new – and potentially better – avenues for treatment in addition to statin drugs.

"While the long-term goal of assessing the benefits of statin treatment in a given individual in the clinic is an important driving force for our grant, the other pay-off that we hope will come sooner is to use these studies to discover new pathways or influences on cholesterol and heart disease risk that are not responsive to statin treatment," Dr. Krauss says.

"If we could identify a basis for persistent risk, we could then see if the genetic information from the functional studies could lead us to new and better targets for therapeutic approaches."

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Tuesday, May 17, 2011 8:19 AM

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