Pharmacogenetics Research Leads the Way to Individualized Therapy

Release Date:
2/6/2006
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Medicines that work wonders for some can be ineffective—or even toxic—to others. Why? A person’s age, weight, lifestyle, and other medicines play a role, but genes also have an important influence. The study of how genes affect drug responses is called pharmacogenetics. The goal of this research is to enable doctors to move beyond the current, one-size-fits-all approach to treatment and toward prescribing the drugs and dosages that will work best for each person.

Birth of a Field

As early as the 1930s, scientists began to realize that natural genetic variations could cause people to respond differently to medicines. Sometimes, these differences can have life-and-death ramifications. For example, the standard, usually effective dose of a drug to treat childhood leukemia can be a fatal overdose or a useless underdose in certain rare individuals.

In the 1950s, scientists started to nail down which genes were responsible for these differences. In 1957, a researcher officially launched the field of pharmacogenetics by publishing a paper that described four early examples, including wide-ranging differences in people’s responses to an antimalarial drug (primaquine) and a muscle relaxant used in surgery (succinylcholine). The term “pharmacogenetics” was coined 2 years later.

In 1967, the New York Academy of Sciences hosted the first international conference on pharmacogenetics, bringing together investigators studying the ever-growing number of exaggerated, unexpected, or ineffective drug responses seen in some people and thought to be due to genetic diversity. Throughout the 1980s, more than 100 other examples were added to the list.

A Strong Foundation

The genetic variations relevant to pharmacogenetics occur in molecules that drugs interact with as they enter, move through, and exit the body. Since its inception in 1962, NIGMS has funded basic studies of the biochemistry, structure, function, and action of these molecules, providing a strong foundation for pharmacogenetics research. In 1982, NIGMS grantee Richard M. Weinshilboum, M.D., of the Mayo Clinic College of Medicine in Rochester, Minnesota, characterized the gene, called TPMT, that is responsible for the different effects of the antileukemia drug mentioned above. This provided one of the first biochemical explanations for varying drug responses. Now, a simple blood test given to children beginning chemotherapy can indicate the appropriate dose of the medicine for each child.

Many pharmacogenetic studies focus on cytochromes P450, a large family of enzymes that metabolize, or break down, medicines. Scientists now recognize more than 20 forms of P450, each of which can have dozens of variants. NIGMS grantee David A. Flockhart, M.D., Ph.D., of the Indiana University School of Medicine in Indianapolis maintains an online list of about 250 drugs and other substances whose activities are determined by P450 enzymes.

The most abundant P450 enzyme found in the liver and intestines is CYP3A, which metabolizes more than half of all drugs. NIGMS-supported scientists have contributed significantly to the understanding of CYP3A and continue to study the molecular details of the enzyme, analyze the prevalence of different gene variants, and correlate these variants with how well people metabolize medicines.

Capitalizing on Opportunities

The Human Genome Project gave scientists access to the sequence of all human genes, opening up new research avenues in pharmacogenetics and other fields. A number of prominent scientists predict that testing of patients for known pharmacogenetic variants will be one of the first clinical applications of genomics.

Recognizing that the time was right for an organized, large-scale effort in pharmacogenetics, NIGMS, in partnership with other NIH components, established the NIH Pharmacogenetics Research Network in 2000. The researchers and physicians in this nationwide collaboration share their data in a knowledge base available to all scientists. In the network’s first 5 years, its scientists focused on the molecular targets of drugs and the enzymes and “gatekeeper” molecules that remove drugs from the body. They made nearly 400 discoveries, including those described below.

Genes Influence Response to Breast Cancer Treatment—Individuals with a specific genetic variation in the drug-metabolizing enzyme CYP2D6 may not respond well to tamoxifen, a widely prescribed treatment for breast cancer. On average, breast cancer survivors with the genetic variation live disease-free for only 4 years after treatment, whereas those without the variation average 11 years. If confirmed, this discovery, by the Flockhart research team, may lead to greater use of genetic tests to identify those women who are most likely to benefit from tamoxifen.


Better Blood Thinning—Every year in the United States, 2 million orthopedic surgery and cardiac patients take warfarin (Coumadin®) to prevent blood clotting. Finding the correct dose is notoriously difficult, and the wrong dose can have life-threatening consequences. Too much causes excessive bleeding and too little could lead to deadly blood clots. Researchers led by Allan E. Rettie, Ph.D., of the University of Washington in Seattle found that differences in a single gene, VKORC1, influence the dose of the drug that is most effective for each person. This discovery is expected to enable faster and more precise warfarin dosing.


Gene Tests to Guide Asthma Treatment—A research team led by Scott T. Weiss, M.D., of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, discovered that genetic variations in certain sets of genes, including those called CRHR1 and ADRB2, affect the way people respond to asthma medicines (inhaled steroids and beta agonists). To help doctors use this discovery to guide treatment decisions, the research team is now developing prototype tests for the gene variants.
In September 2005, NIGMS renewed the Pharmacogenetics Research Network and Knowledge Base, promising a steady stream of advances during the next 5 years. NIGMS also takes seriously the ethical, legal, and social implications of the use of pharmacogenetic information and seeks to support research in these areas.

Together with a number of other NIH components, NIGMS is supporting the International HapMap Project a worldwide collaboration of scientists that is developing a map of all the common variations in the human genome. The HapMap is already helping researchers find genes affecting health, disease, and drug responses.

Future Promise

As scientists gain a better understanding of the genes involved in different drug responses and develop tests for relevant gene variants, pharmacogenetics will steadily move from the bench to the bedside. Commercial tests are already available for several enzymes whose variations result in different drug responses, including two members of the P450 family (CYP2D6 and CYP2D9) and TPMT.

The U.S. Food and Drug Administration has begun to incorporate pharmacogenetic considerations in the prescribing information for some drugs. For example, in response to NIGMS-supported research led by Mark J. Ratain, M.D., of the University of Chicago, the label of an anticancer drug called irinotecan was changed in the summer of 2005. The new label encourages doctors to use a lower starting dose for patients known to have a genetic variation that increases their risk for life-threatening reactions to the drug.

In the future, pharmacogenetics researchers hope not only to predict and adjust for drug effects caused by single genes, but to do the same in treating more complex conditions like high blood pressure and diabetes that result from a combination of genes. The ultimate goal is for doctors to prescribe to all of their patients the right dose of the right medication the first time. This is echoed by HHS Secretary Michael O. Leavitt in his 500-Day Plan, in which he envisions “a nation in which. . .medications are safer and more effective because they are chosen based on the patient’s personal characteristics.”