Dr. Krauss Receives $13.2M NIH Grant

Children's Hospital Oakland Research Institute (CHORI) Senior Scientist Dr. Ronald Krauss has received a five-year, $13,184,000 grant from the National Institutes of Health (NIH) for precision medicine research in statin response. The grant, awarded September 7 from the NIH's National Institute of General Medical Sciences (NIGMS), will enable Dr. Krauss and his colleagues to apply a multi-disciplinary approach to identify genetic determinants of the efficacy of statin drugs in reducing the risk of cardiovascular disease (CVD), as well as the risk for adverse effects of statins, specifically myopathy and type-2 diabetes.

To this end, Dr. Krauss and his team have created a Center for Pharmacogenomics in Precision Medicine with a research program that utilizes an innovative "systems" approach. This will incorporate complementary genomic, transcriptomic, and metabolomic tools, together with studies in cellular and animal models, and innovative informatics models. In carrying out this research program, Dr. Krauss will be working closely with Dr. Marisa Medina at CHORI, who leads one of the Center's three projects.

Through queries of electronic medical records, Dr. Medina and colleagues will recruit statin users from Kaiser Permanente of Northern California who have experienced adverse outcomes - namely, individuals for whom statins have not prevented a major adverse coronary event, such as a heart attack, as well as those who developed either myopathy or type-2 diabetes while on treatment. Using cell lines established from these individuals, as well as from matched controls, i.e. statin users who have not had an adverse outcome on treatment, they will identify genes and metabolites whose expression differs between cases and controls. Dr. Medina pioneered the approach of performing molecular profiling of patient-derived cells for pharmacogenomic discovery.

The Center also includes investigators from UCSF, UC Berkeley, UCLA, University of Washington, and Penn State. The team's ultimate goal is to enable use of the information derived from this program to identify new biomarkers that modulate the multiple actions of statins and that can be used to guide more effective use of this widely used class of drugs.

"Our previous research has shown that investigation of molecular and cellular mechanisms influenced by statins can lead to identification of genetic variants that contribute to clinically important differences in response to statin treatment," says Dr. Krauss. "This grant allows us to extend this approach to identify genetic variants and molecular mechanisms that influence statin-related myopathy and new-onset diabetes."

Statins are among the most widely prescribed drugs in the western world, used to treat elevated cholesterol levels and reduce the risk of cardiovascular disease. While statins are highly effective and generally safe, adverse effects occur in a small proportion of users, which represents a large number of individuals due to statins' widespread use. In some individuals, statins adversely affect muscle, with symptoms ranging from mild pain to the breakdown of muscle tissue. Other statin users may be at increased risk for type-2 diabetes.

Dr. Krauss's grant is one of three "P50" grants recently awarded by NIGMS to establish specialized research centers for pharmacogenomics in precision medicine. Dr. Krauss has been one of the principal investigators in the Pharmacogenomics Research Network (PGRN), a network of scientific groups focused on understanding how a person's genes affect his or her response to medicines that has been supported since 2000 by the NIH.

"These grants allow the investigators to pursue a range of basic, clinical and translational research that will contribute to a fundamental understanding of how to use drugs safely and effectively, which is an important aspect of precision medicine," said NIGMS' Rochelle M. Long, Ph.D., who directs the program.

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