Learning How Genes Affect People's Responses To Medicines

As the high-profile effort to decipher the human genome nears completion,scientists nationwide are launching another ambitious project - this time tolearn how variations in genes affect people's responses to drugs. Differencesof a single "letter" among many thousands in the DNA instructions of a gene arethought to often affect drug response. The emerging research, in the fieldknown as pharmacogenetics, is expected to revolutionize the way drugs aredesigned and tested, boost the effectiveness of drug treatments and cut thelikelihood 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 theNational Institutes of Health in the first phase of a major newpharmacogenetics research initiative. The national project aims to identify thegenetic differences that determine why some people can be successfully treatedwith a drug while others with the same condition remain unaffected or are evenharmed by the drug. The four-year UCSF study involves laboratory and clinicalresearch to determine how natural genetic variation affects the performance ofhuman proteins known as membrane transporters which act as cellulargatekeepers, controlling whether drugs get into the blood stream.

"Our ultimate goal is to able to read someone's DNA and know what drugs to useand at what doses, as well as which drugs to avoid," says Kathleen Giacomini,PhD, professor and chair of biopharmaceutical sciences at UCSF and the leaderof the transporter study. "Transporter proteins are one of the keys to drugresponse, and that's why we are looking for the genetic variants among them."

Giacomini, a leader in studies of how transporters affect absorption andelimination of drugs in the body, last year was awarded the PharmaceuticalScientist of the Year Award by the International Pharmaceutical Federation inrecognition of her research.

The UCSF project, totaling about $3.2 million in its first year, is funded bythe National Institute of General Medical Sciences (NIGMS). It will focus onvariants in transporter genes that underlie the response to many frequentlyused drugs, including responses to antidepressant and anticancer drugs. Theproject 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 ethnicallydiverse sample of 450 people as well as other study populations. Researcherswill then test the performance of these transporter variants in cell cultures,and finally, clinical researchers will determine if people with those variantsrespond differently to drugs in a clinically significant way.

Geneticist Ira Herskowitz, PhD, professor of biochemistry and biophysics atUCSF and a co-leader of the UCSF project, stresses that a rich range ofresearch expertise is needed to determine how genes control drug response.

"The excitement of this project is bringing together people with diverseresearch skills, from pharmaceutical scientists to molecular and populationgeneticists and clinicians, to tackle questions about how people's genesinfluence their response to drugs," he says.

Data from the UCSF research and that of the other institutions involved in theNIH-funded study will go immediately into a national database housed andoperated by scientists at Stanford University School of Medicine, recipients ofa $1.6 million grant for the first year of this project. The PharmacogeneticsKnowledge Base (PharmGKB), as it is being called, will serve as the sharedinformation library for all scientists in the research network to easecollaborative research in this critical emerging field and to speedapplications.

Other institutions supported in the NIH initiative, and the funding for theirfirst year, are:

* Brigham and Women's Hospital in Boston: $2.6 million for a multicenter effortto discover genes involved in widely varying responses to asthma treatments.

* Georgetown University Medical Center: $1.3 million to study how geneticdifferences between people may explain variable response to tamoxifen.

* UCLA: $285,000 for a one-year pilot project to search for genetic differencesinvolved in how Mexican-Americans respond to two antidepressants.

* Yale University: $421,000 to develop a Web-based database tool to incorporateexisting pharmacogenetic knowledge into the PharmGKB library.

* University of Chicago: $2.5 million for a multicenter effort to examine howthe benefits and side effects of certain chemotherapy drugs vary among people.

* University of Houston Law Center: $322,000 to study the ethical, legal andsocial implications of using pharmacogenetics information, particularlyregarding race and ethnicity.

* The Mayo Foundation in Rochester, Minn.:$576,000 to search for variations ingenes encoding proteins known to be important in how the body handles a widerange of medicines, hormones and chemical messengers.

NIH is planning to award additional pharmacogenetics research projects insubsequent years.

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An NIGMS news release on the new initiative is posted on the institute's website at http://www.nigms.nih.gov/news/releases/pharmacogenetics.html.More detailed information about the initiative is athttp://www.nigms.nih.gov/funding/pharmcogenetics.html.

An online, text-only version of an NIGMS lay-oriented brochure aboutpharmacogenetics, "Medicines for YOU" is posted athttp://www.nigms.nih.gov/funding/medforyou.html.