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UNC's Global Personalized Medicine Initiative Expands to Eastern Europe, Preps PGx World Map


By Molika Ashford

Greece's Golden Helix Institute has become the new hub for Eastern Europe in the Pharmacogenomics for Every Nation Initiative — a University of North Carolina program to help countries incorporate genomic risk data into medication decisions.

PGENI is led by UNC Chapel Hill's Institute for Pharmacogenomics and Individualized Therapy in partnership with regional centers around the world. The effort is now completing genotyping of populations in about 25 countries and hopes to submit their pharmacogenomics global map of common SNPs in these world regions for publication later this year.

"With Eastern Europe we wanted to have an active group," Howard McLeod, a UNC professor and head of PGENI, told PGx Reporter.

"I was very convinced after talking with [George Patrinos of the Golden Helix Institute], that he and his institution were the right partners for that part of the world. And since we've started, he's certainly confirmed that that was a correct assumption," McLeod said. "Often scientists don’t understand anything about public policy, so finding an internationally recognized scientist who can also be thinking about how to positively influence policy is a rare find."

The Golden Helix Institute of Biomedical Research supports scientific research and education in the field of genomic medicine and is supervised by a scientific advisory council of leaders in the translational medicine field. Patrinos, a member of this advisory council, approached McLeod at a conference to propose joining the initiative to expand PGENIs efforts in the region.

Access to Eastern Europe expands PGENI's current coverage to more countries that the initiative considers likely to benefit most from the use of pharmacogenomic data in prioritizing drugs. According to McLeod, drug choice is a higher stakes endeavor for poor or developing countries that have a limited amount of money than it is for more developed countries where many drugs might be available for each indication. "If they purchase a drug they really need it to work because there's no plan B or C," he said.

In addition to the Golden Helix Institute, PGENI also has partner centers in South Africa, Ghana, Mexico, Brazil, China, and India. McLeod said that each of these regional centers is responsible for initiating genotyping studies involving local populations and advising countries on how the resulting pharmacogenonetic data might be used to prioritize drugs in national formularies.

PGENI's model, McLeod said, is to "look at the genetic incidences of causative risk or efficacy markers in a given population and then try to individualize the policy rather than individualize for the person."

"If a country can only afford a small number of drugs for any particular disease, really any data at all will cause you to pick one versus another when they're equal in terms of clinical trials," he said. This makes the population-based approach much more valuable. "When you look at how high stakes the decision is around medicines, it's critical that they have some data, as opposed to the current approach, which is using [data from Western European populations]," he said.

Once a country has expressed interest in participating in the initiative, McLeod said, subgroups are identified in collaboration with local academics who understand how local populations self-identify, creating locally accurate divisions for genotyping.

"Our ideal is to get 500 blood samples from each of these groups," McLeod said, "That way we have power to detect at least a doubling of risk."

The initiative's centers are primarily using the Affymetrix DMET plus chip, which includes 1,936 markers for 225 genes associated with drug metabolism (PGx Reporter 01/13/2010).

PGENI compares the SNP associations for a particular region with World Health Organization's "clinical decision trees" to come up with a prioritized list of which medicines should be chosen first, second, and third for each indication. "We're often talking about a list of over two hundred drugs, and about 270 different disease indications," McLeod said.

According to McLeod, PGENI hopes to be ready by later this summer to submit its global PGx map for publication, which will reveal regional patterns of risk that the group has identified.

"Our hope is to have the genomic analysis completed by the end of May, to have the statistical analysis completed by June, and to have it submitted [for publication] by the end of July," he said.

"We’re currently finishing up the analysis of some of our southern African and South American populations, and at that point we'll have a map of metabolism and transport variants that goes across the major countries throughout the world. We'll have about 25 different countries represented," McLeod said.

With the addition of Greece's Golden Helix Institute, several Eastern European countries have also begun to be genotyped, including Serbia, Poland, and Greece itself, McLeod said.

'Very Odd Places'

McLeod said initial genotyping results have already revealed some interesting population differences. "It's one of those situations where regions are more similar than they are different, but there are still clinically relevant differences within each region."

One interesting result involves thiopurine methyltransferase polymorphism, which is associated with increased risk of toxicity for a number of different drugs. In PGENI's results, TPMT risk alleles showed up in "very odd places," McLeod said. "We see the highest in Ghana, Bulgaria, and Peru."

"I have no hypothesis that ties those three places together," he said. "And there are many countries we haven't looked at, so it could be that there is a logical reason for it, but at the moment for some reason there is an excess in the risk alleles in those places."

According to McLeod, the group had hoped there would be enough regionalism that investigators wouldn't have to assess every country individually. "But what we're finding [is] a fairly strong justification for looking within each country if that country wants to make decisions about public health," he said.

Though the initiative has not had to turn down a country interested in becoming part of the project, McLeod said the group will inevitably collide with some financial limitations.

"When you look at the countries that meet our criteria for needing the most help, there are 104 countries," he said. "If there was a huge growth in the number of countries that were interested we could not currently financially cope with it."

McLeod said the group has approached funding groups like the Bill and Melinda Gates Foundation that might allow PGENI to help more countries join up. "We are well aware that as we're showing success more countries will be interested and that's why we're putting so much effort now into trying to shore up our regional centers, make sure we have the capacity, [and] build up the financial infrastructure," said McLeod.

Nations that are already on board are also now coming to the point where they are making decisions about how to use the genomic data produced by PGENI, McLeod said.

"From our interactions with Ghana and with some of the other countries we've been working with the longest, there have been areas of risk identified that were not anticipated and that have resulted that in either increased vigilance…or [they] actually change the recommendations."

Tanzania for example, McLeod said, switched its recommendations away from the malaria drug amodiaquinen, after PGENI identified that the country's population has an excess of a CYP2C8 variant linked with greater toxicity.

From the start, McLeod said, countries have been very interested in the possibility of investment from pharmaceutical companies. He explained that the reason PGENI has avoided working with the private sector thus far is that many governments and organizations the group works with, especially the WHO, would prefer for there not to be drug company involvement.

At the same time, he said, "There is a lot of interest in using this data either to identify areas where clinical trials might be enriched … [or] one could then think about strategies for marketing the drug without having to require individual patient genotyping."

While the initiative is currently holding off on any interaction with industry, McLeod said it plans to interact more once it has provided recommendations for participating countries.

PGENI is also looking into ways to expand its mission to subpopulations in the US, which face similar problems in harnessing pharmacogenomic data to help them make drug decisions, according to McLeod. US minority groups are more likely to respond poorly to therapies and have a higher incidence of hospital admissions due to poor efficacy and adverse events, he said.

"Now we're now starting to interact with some of the Native American groups in the United States, and also completing a study of the US Hispanic populations. We really realized we’re working with nations across the world, but not looking at the nations within our country," he said.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at mashford [at] genomeweb [.] com.

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