Five-Year Perspective on the Pharmacogenetics Research Network

The Pharmacogenetics Research Network (PGRN) is a nationwide collaboration of scientists focused on understanding how genes affect the way a person responds to medicines. The long-term goal of the network is to make information available to doctors that will ensure the right dose of the right medicine the first time for everyone.  Since its inception 5 years ago, PGRN scientists have studied genes and medications relevant to a wide range of diseases, including asthma, depression, cancer, and heart disease.

 

 

Project Period: April 2000 to August 2005

Funding: $140 million (funded largely by the National Institute of General Medical Sciences and the National Heart, Lung, and Blood Institute, with additional support from the National Cancer Institute, the National Library of Medicine, the National Institute of Environmental Health Sciences, and the National Human Genome Research Institute).

 

Number of Centers: 12

Number of Individual Research Grants: 1

Publications in Scientific Journals: more than 380

Genetic Variations (Single Nucleotide Polymorphisms or SNPs) in Database: more than 1 million

 

 

PGRN researchers have made several discoveries that are likely to improve the treatment of childhood leukemia. They looked across the entire genome to discover 124 genes that can explain why some leukemias are resistant to chemotherapy drugs. They also found that differences in two genes (GSTM1 and TYMS) can lead to a higher risk for leukemia relapse. Children with these high-risk genes may benefit from more aggressive therapy. On the flip side, the researchers discovered two other gene variations (VDR and another variant of TYMS) that predispose to a serious side effect when the children are treated with steroids, one of the standard therapies for leukemia. Studies are under way to test whether dosing should be modified in children with these gene variations. (Mary V. Relling, Pharm.D., The Pharmacogenetics of Anticancer Agents center)

 

One finding by PGRN researchers spurred changes in the label of irinotecan, a drug approved in 1996 that treats colorectal, lung, and other cancers.  Approximately 10 percent of the North American population have two copies of a genetic variation called UGT1A1*28 that puts them at higher risk for serious, even life-threatening reactions to irinotecan. In the summer of 2005, the label of the drug was changed to include information about UGT1A1*28 and to encourage doctors to use a lower starting dose for patients known to have this variation. (Mark J. Ratain, M.D., The Pharmacogenetics of Anticancer Agents center)

 

Gene Tests Could Indicate Best Asthma Treatment

PGRN researchers have learned details about how variations in certain sets of genes (including CRHR1 and ADRB2) affect the way people respond to asthma medicines, specifically inhaled steroids and beta agonists. Testing for these genes will help doctors recommend the best treatment for individual patients. PGRN scientists expect to develop prototype tests for the gene variants within a year. (Scott T. Weiss, M.D., The Pharmacogenetics of Asthma Treatment center)

 

Genes Shed Light on Sudden Death from Irregular Heartbeats

 Almost everyone experiences harmless irregular heartbeats, called arrhythmias, from time to time. But about 4 million Americans—most over age 60—have recurrent arrhythmias that, in some cases, can cause sudden death. PGRN scientists tracked down gene variants that put people at higher risk for fatal heart arrhythmias. This information will help doctors target high-risk patients for more aggressive screening and preventive medications. Because some arrhythmias are brought on by medications that treat conditions as diverse as bacterial infection and psychiatric disease, the research will also help doctors tailor medications to individual patients. In the future, it may even lead to new drugs based on gene targets. (Daniel M. Roden, M.D., The Pharmacogenomics of Arrhythmia Therapy center)

Genes Influence Response to Breast Cancer Treatment

A major focus in pharmacogenetics research is on a large group of enzymes that process many medications in the body. PGRN researchers studying women with breast cancer found that individuals with a specific genetic variation in one such enzyme (CYP2D6) don’t respond as well as those without the variation to tamoxifen, a widely prescribed drug used to treat breast cancer. On average, breast cancer survivors with the CYP2D6 variation live disease-free for only 4 years after treatment, whereas those without the variation average 11 years. This discovery may lead to greater use of genetic tests to determine which women are most likely to benefit from tamoxifen. (David A. Flockhart, M.D., Ph.D., The Consortium on Breast Cancer Pharmacogenomics)

 

Every year in the United States, warfarin is used to prevent blood clotting in 2 million people, including those with heart disease and those recovering from orthopedic surgery. Warfarin is tricky to prescribe, because too much causes excessive bleeding and too little could allow dangerous blood clots to form. PGRN researchers discovered that differences in a gene (VKORC1) influence the dose of warfarin that is most effective for each person. This information ultimately could help doctors determine each patient’s warfarin dose more quickly and precisely, without trial-and-error. (Howard L. McLeod, Pharm.D., The Functional Polymorphism Analysis in Drug Pathways center)

 

Transporter proteins embedded in cell membranes not only bring essential material into cells, but they purge cells of wastes, drugs, and other chemicals. PGRN researchers have found more than a thousand genetic differences in 40 of these transporters. The genetic changes may affect how people respond to a wide variety of drugs. In the largest and most comprehensive study of its kind, PGRN researchers are investigating how these transporter genes affect people’s responses to the antidepressants paroxetine and fluoxetine, drugs that are better known by their brand names, Paxil® and Prozac®. (Kathleen M. Giacomini, Ph.D., The Pharmacogenetics of Membrane Transporters center)

 

Nearly everyone who takes medicines should benefit from PGRN researchers’ discovery of common variations in CYP3A5. This gene is extremely important because it is involved in the body’s handling of more than half of all medications, yet it has been difficult to study because it has so many variants. Differences in this gene may help explain racial and ethnic differences in drug response, especially for medications used to treat high blood pressure. PGRN scientists found that some of the genetic differences are hidden in an unexpected place: in “non-coding” regions deep in the gene. (Daniel T. O'Connor, M.D., The Autonomic Pharmacodynamic Pharmacogenomics center)

 

PharmGKB: Bringing It All Together

A key component of the PGRN is the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), a shared online resource that contains pharmacogenetics data from the PGRN and others and is freely available to the entire scientific community. PharmGKB integrates carefully curated and annotated information about genes, drugs, and diseases, including data about more than 10,000 unique human gene variations involved in drug responses. In addition to facilitating data sharing, PharmGKB helps researchers identify and fill in knowledge gaps. To protect the privacy of research study participants, names and other identifying information are not stored in this library. (Russ B. Altman, M.D., Ph.D., The Pharmacogenetics and Pharmacogenomics Knowledge Base)