As the high-profile effort to decipher the human genome nears completion, scientists nationwide are launching another ambitious project -- this time to learn how variations in genes affect people's responses to drugs. Differences of a single "letter" among many thousands in the DNA instructions of a gene are thought to often affect drug response. The emerging research, in the field known as pharmacogenetics, is expected to revolutionize the way drugs are designed and tested, boost the effectiveness of drug treatments and cut the likelihood of side effects.
A team of more than 20 scientists at UC San Francisco has received an $11.9-million research grant -- the largest among nine awarded this week by the National Institutes of Health in the first phase of a major new pharmacogenetics research initiative. The national project aims to identify the genetic differences that determine why some people can be successfully treated with a drug while others with the same condition remain unaffected or are even harmed by the drug. The four-year UCSF study involves laboratory and clinical research to determine how natural genetic variation affects the performance of human proteins known as membrane transporters which act as cellular gatekeepers, controlling whether drugs get into the blood stream.
"Our ultimate goal is to able to read someone's DNA and know what drugs to use and at what doses, as well as which drugs to avoid," says Kathleen Giacomini, PhD, professor and chair of biopharmaceutical sciences at UCSF and the leader of the transporter study. "Transporter proteins are one of the keys to drug response, and that's why we are looking for the genetic variants among them." Giacomini, a leader in studies of how transporters affect absorption and elimination of drugs in the body, last year was awarded the Pharmaceutical Scientist of the Year Award by the International Pharmaceutical Federation in recognition of her research.
The UCSF project, totaling about $3.2 million in its first year, is funded by the National Institute of General Medical Sciences (NIGMS). It will focus on variants in transporter genes that underlie the response to many frequently used drugs, including responses to antidepressant and anticancer drugs. The project will first determine the amount of variation, -- usually in the form of "single-letter" differences known as single-nucleotide polymorphisms, or SNPs -- in the 25 different transporter genes by examining DNA from an ethnically diverse sample of 450 people as well as other study populations. Researchers will then test the performance of these transporter variants in cell cultures, and finally, clinical researchers will determine if people with those variants respond differently to drugs in a clinically significant way.
Geneticist Ira Herskowitz, PhD, professor of biochemistry and biophysics at UCSF and a co-leader of the UCSF project, stresses that a rich range of research expertise is needed to determine how genes control drug response. "The excitement of this project is bringing together people with diverse research skills, from pharmaceutical scientists to molecular and population geneticists and clinicians, to tackle questions about how people's genes influence their response to drugs," he says.
Data from the UCSF research and that of the other institutions involved in the NIH-funded study will go immediately into a national database housed and operated by scientists at Stanford University School of Medicine, recipients of a $1.6 million grant for the first year of this project. The Pharmacogenetics Knowledge Base (PharmGKB), as it is being called, will serve as the shared information library for all scientists in the research network to ease collaborative research in this critical emerging field and to speed applications.
Other institutions supported in the NIH initiative, and the funding for their first year, are:
. Brigham and Women's Hospital in Boston: $2.6 million for a multicenter effort to discover genes involved in widely varying responses to asthma treatments.
. Georgetown University Medical Center: $1.3 million to study how genetic differences between people may explain variable response to tamoxifen.
. UCLA: $285,000 for a one-year pilot project to search for genetic differences involved in how Mexican-Americans respond to two antidepressants.
. Yale University: $421,000 to develop a Web-based database tool to incorporate existing pharmacogenetic knowledge into the PharmGKB library.
. University of Chicago: $2.5 million for a multicenter effort to examine how the benefits and side effects of certain chemotherapy drugs vary among people.
. University of Houston Law Center: $322,000 to study the ethical, legal and social implications of using pharmacogenetics information, particularly regarding race and ethnicity.
. The Mayo Foundation in Rochester, Minn.:$576,000 to search for variations in genes encoding proteins known to be important in how the body handles a wide range of medicines, hormones and chemical messengers.
NIH is planning to award additional pharmacogenetics research projects in
subsequent years.
An NIGMS news release on the new initiative is posted on the institute's web site at http://www.nigms.nih.gov/news/releases/pharmacogenetics.html. More detailed information about the initiative is at http://www.nigms.nih.gov/funding/pharmcogenetics.html. An online, text-only version of an NIGMS lay-oriented brochure about pharmacogenetics, "Medicines for YOU" is posted at http://www.nigms.nih.gov/funding/medforyou.html.