| 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 (http://medicine.iupui.edu/flockhart/).
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
(http://www.nigms.nih.gov/pharmacogenetics)
in 2000. The researchers and physicians in this nationwide collaboration
share their data in a knowledge base available to all scientists
(http://www.pharmgkb.org/).
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 do 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. 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 (http://www.hapmap.org/),
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 (http://www.hhs.gov/500DayPlan/500dayplan.html),
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.”
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