Researchers awarded $14 million for two precision health projects

Teri Klein and Russ Altman have received NIH funding to expand two ongoing projects that publish information about the connection between patients’ genetics and their responses to prescription drugs.

- By Jennie Dusheck

Russ Altman

The National Institutes of Health has awarded School of Medicine researchers Teri Klein, PhD, and Russ Altman, MD, PhD, $14 million in funding for two projects that will advance the practice of precision health.

Altman, professor of bioengineering, of medicine and of genetics, and Klein, senior research scientist, are the principal investigators for a four-year, $10 million grant from the National Institute of General Medical Sciences to expand their premier precision-health resource PharmGKB knowledge base, now in its 15th year. PharmGKB provides comprehensive information about how genetics affects drug response in individuals.

People can react very differently to the same drugs. For example, the enzyme CYP2D6 is involved in metabolizing hundreds of prescription drugs. One drug that CYP2D6 metabolizes is the opiate painkiller codeine, which CYP2D6 converts into morphine — the active form of the painkiller. Most people have just two copies of the CYP2D6 gene, but some of us have more. Extra copies of the gene pump out so much of the enzyme that codeine and other drugs are metabolized far more rapidly than prescribing physicians expect. People with more than two copies of the gene can convert a standard dose of codeine to morphine so rapidly that they may overdose.

Some people have the opposite problem. The CYP2D6 gene comes in more than 160 different versions, or alleles, and some of these versions encode an enzyme that doesn’t metabolize codeine very well. People with such variants turn codeine to morphine slowly, or not at all, so the codeine doesn’t ease their pain. CYP2D6 is just one of hundreds of genes that influence drug response currently cataloged at PharmGKB.

PharmGKB is part of a nationwide program called the Pharmacogenomics Research Network spearheaded by the NIGMS. Klein and Altman created PharmGKB in 2000 — collecting, curating and disseminating information about the many ways that humans vary in how they respond to different drugs. The knowledge base includes, for example, gene/drug associations, dosing guidelines and drug labels.

Teri Klein

PharmGKB has organized genetic information derived from nearly 10,000 scientific papers and documented nearly 13,000 associations between specific alleles and drug response phenotypes. With the new $10 million grant, Klein, director of PharmGKB, and Altman plan to expand the repository; tackle drug responses involving multiple genes; and reprogram the knowledge base so it is accessible to users with different levels of scientific sophistication.

Genotype-based recommendations for clinicians are essential to bring pharmacogenomics into the clinic. By weaving together the increasingly widespread availability of genetic test results and personalized drug prescriptions, PharmGKB acts as a critical driver of precision-health practice.

The second grant is a three-year, $4 million grant from the NIGMS and the National Human Genome Research Institute to Klein and co-principal investigator Mary Relling, PharmD, chair of pharmaceutical sciences at St. Jude Children’s Research Hospital, for the Clinical Pharmacogenetics Implementation Consortium.

CPIC publishes clinical guidelines that teach health-care providers how to use information about their patients’ genetics to guide and optimize drug prescriptions. The consortium has produced more than a dozen detailed, peer-reviewed and regularly updated gene/drug clinical guidelines.

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