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SAEC Partners with Shanghai University to Explore Ethnic Variation in Adverse Drug Reactions


By Molika Ashford

The International Serious Adverse Events Consortium this week announced a partnership with Shanghai Jaio Tong University to research severe drug reactions in Chinese populations, expanding the group's understanding of the impact of ethnic diversity on genomically influenced adverse events.

According to Arthur Holden, chairman of the SAEC, the Shanghai collaboration is part of the consortium's second phase of research to study drug reactions that have a strong immunologic underpinning, such as drug-induced liver injury, hypersensitivity, and serious skin rashes.

The SAEC was founded in 2007 and is now funded by 10 major pharmaceutical companies, according to Holden, with support and guidance from the US Food and Drug Administration. The group aims to identify and validate genomic variants associated with drug-induced serious adverse events (PGx Reporter 06/03/09).

"The collaboration with Shanghai University is an important one for a couple of different reasons. One is, it gives us a strong translational research alliance in China [with] a network of roughly 30 large hospitals, including the [General Hospital of the People's Liberation Army] in Beijing, which I believe to be the largest hospital in the world, with 4,000 beds," Holden told PGx Reporter this week.

"Having this network of clinical institutions, where we can recruit patients that have exposure to various drugs and might have these effects, really gives us a wonderful opportunity to build some ethnic diversity into this research," he said.

Thus far, most of the consortium's data has come from Caucasian subjects — not by design, but simply because most research available to the group has been on European and American patients, Holden said. A partnership with Chinese hospitals offers the SAEC a big step toward gaining a more complete picture of the genomic underpinnings of severe drug reactions.

The consortium has inked several partnerships with other academic institutions, including one signed last year with the UK's University of Liverpool and Newcastle University intended to scale up geographic and ethnic diversity in its work to validate risk alleles in subsets of patients treated with a particular drug or classes of drugs (PGx Reporter 09/15/10).

With the Shanghai researchers, projects will be coordinated by the university's Bio-X institute, the group announced. Holden said that the first phase of the partnership, expected to last approximately two years, will focus on drug-induced liver injury, hypersensitivity and skin rashes.

"We'll basically be providing support for the building of cohorts and the partnering on of genotyping and sequencing in conjunction with our other research efforts," Holden said. "This helps them move [their research] along, and helps us build a more comprehensive understanding of what might be going on here scientifically."

Holden did not detail the group's plans for examining these three main adverse reactions in China, but said the SAEC is definitely interested in looking at a variety of anti-tuberculosis drugs and their associations.

"Clearly a number of antiviral and antibacterial compounds have a higher than average propensity [for] these genetic effects to take place," Holden said. "So we have a bias in that area. But, on the other hand, we just need more experience until we know what we're going to get."

The SAEC is also exploring how it might use whole-genome sequencing to enhance the information gleaned from the genome-wide association studies that have driven discoveries so far, according to Holden.

Last year, the SAEC and Duke University partnered to investigate rare genetic variants associated with adverse events in people taking the antipsychotic drug clozapine using a whole-genome sequencing approach (PGx Reporter 01/28/10).

Holden said these sequencing pilots are still "in evolution" for the SAEC. "We'll be evolving that, and the focus is to try to add ethnic diversity to the core areas we're particularly interested in," at the same time, he said.

Ethnic diversity is key to moving from the discovery and validation studies ongoing in the consortium, to eventually creating commercial tests or actionable guidelines for prescribing drugs with possible adverse effects, Holden said, because the frequency of variants associated with these events can be so unpredictable across and within ethnic groups.

"We see differences in the genetics of drug-induced liver injury associated with augmentin," Holden said. "From what we know so far studying common variation, the allele differs depending on whether one is northern or southern European. And then, there are cases where we see that same allele… in the case of abacavir for HIV, is strongly penetrant and predictive across a number of ethnic groups."

"The reality is each of these situations has to be researched and studied over time. And that's why no company and no one test can possibly do that. There's too much variation out there," Holden said.

To appropriately deal with such complexity, Holden said he imagined the SAEC's research eventually leading to an assay combining the full range of known risk markers for adverse reactions.

"As we evolve, I hope what will happen, once we being to see over more and more ethnic groups and more and more drugs, [is] we're going to be able to profile a bunch of risk alleles that may vary over ethnicity and drug [but] carry an increased risk."

Currently, he noted, "we don’t know any of that; we just fire away the drugs."

According to Holden, the SAEC's role is to create a scientific baseline to open up commercial opportunities for what he envisions as a "one-time assessment" of drug reaction risk for each patient.

"If you're able to put all of [these alleles] on a common chip and use that just once in a patient's life and ideally store it in one's electronic health record and then be able to refer to those predispositions … through ones lifetime, then you can actually begin to manage some of that risk of these adverse responses," he said.

"That's really the game that we're playing."

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