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Consortium Explores Sequencing to Study Rare Serious Adverse Reactions to Drugs

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By Julia Karow

Following several genome-wide association studies, the International Serious Adverse Event Consortium, a non-profit venture that aims to identify genetic variants associated with adverse reactions to drugs, is currently testing exome sequencing in several pilot projects to see what additional insights the results may provide.

The SAEC was founded in mid-2007 and seeks to identify and validate DNA variants that are useful in predicting the risk of rare drug-induced serious adverse events. Members include the Wellcome Trust as well as several pharmaceutical companies, such as Abbott, Amgen, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Sanofi-Aventis, and Takeda.

During its first few years, SAEC conducted genome-wide association studies on several cohorts of individuals who had experienced serious adverse drug reactions, including drug-related liver toxicity; serious skin rash, in particular Stevens-Johnson syndrome; and cardiac arrhythmia. Last year, the consortium published its first paper, showing that a variant of the HLA-B gene, which is part of the major histocompatibility complex, is associated with flucloxacillin-induced liver injury.

In order to more comprehensively analyze genetic variants associated with adverse drug events, the SAEC earlier this year launched two pilot projects to explore exome sequencing, using the Illumina platform, and is currently organizing a third one.

"Our intent is to have sequencing pilots to tie onto each of the GWAS studies that we have completed," SAEC Chairman and CEO Arthur Holden told In Sequence last week.

The decision to start with exome sequencing rather than whole-genome sequencing was mostly based on economics. "It was really a cost-benefit tradeoff," Holden said. "We felt that an incremental approach was a better [approach]. We can continue to add onto the dataset as we go forward," and as the cost of sequencing declines.

In addition to cost, the complexity of data handling and analysis was a reason to start off with exome sequencing. "Right now, given what we're able to do with the exome studies, it's going to be a while until we jump into the whole genome," he said.

Sequencing for the first pilot, in collaboration with the Center for Human Genome Variation at Duke University, is already completed and the data analysis is ongoing, Holden said. The goal of this project, which SAEC launched in January, is to identify rare genetic variants that are predictive of clozapine-induced agranulocytosis, a failure of the bone marrow to produce sufficient neutrophils that leads, to a reduced immune response. Clozapine is an antipsychotic used to treat schizophrenia, and CIA occurs in fewer than 2 percent of patients receiving the drug. Because of this risk, patients have to undergo a weekly lymphocyte count.

The pilot project involves exome sequencing of a cohort of 25 CIA samples that were donated to the SAEC last year by PGx Health, a division of Clinical Data, as well as a number of controls. "We hope that understanding the genetics of CIA will not only reduce its occurrence, but also allow wider use of clozapine," said David Goldstein, director of Duke's Center for Human Genome Variation, in a statement at the time of the project launch.

Holden said that it is too early to comment on the results, noting that the analysis is complex, in part due to the fact that it is difficult to find sufficient and well-matched controls.

This summer, SAEC launched a second pilot, in collaboration with the Broad Institute, to use exome sequencing to study rare variants associated with Augmentin-induced liver injury. Augmentin, which is marketed by GlaxoSmithKline to treat a wide variety of bacterial infections, consists of the antibiotic amoxicillin and the beta-lactamase inhibitor clavulanate potassium, which prevents bacteria from breaking down amoxicillin. Drug-induced liver injury is a rare side effect of Augmentin, as well as other medications.

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The SAEC, through a previous GWAS study, has already discovered associations between drug-induced liver injury and the MHC. "By researching the genetics of Augmentin-induced liver injury, we hope to further our understanding into the genetics of immunologically mediated adverse drug responses," said Holden in a statement at the project launch in June.

Through collaborations with three drug research networks, SAEC has collected almost 500 samples from patients who experienced drug-related liver injury, and Holden said that for the pilot the exomes of about 200 cases are currently being sequenced by researchers at the Broad, led by Mark Daly, who directs computational biology for the institute's medical and population genetics program. The Broad will also analyze the data, using in-house controls of unaffected individuals.

The SAEC is currently in the process of organizing a third sequencing pilot project, Holden said, which will focus on the genetics of drug-induced cardiac arrhythmia associated with a prolonged QT interval.

It has not yet announced a collaborator for that project. But in 2009, the consortium launched a collaboration with the Drug Safety Research Unit at St. George's University of London and the Drug-Induced Arrhythmia Risk Evaluation network to study drug-induced torsades de pointes, a cardiac arrhythmia associated with a prolonged QT interval, using array-based genotyping. It released the first data from this project, comprising 103 cardiac arrhythmia cases, on its website last month.

Like its GWAS projects, the SAEC plans to make the data from its sequencing pilots available to qualified researchers on its website prior to publishing it in a journal, though there will be an embargo of about a year until outside researchers may publish analyses of the data.

In addition, for the sequencing pilots, the consortium is seeking to partner with other groups on the data analysis. "The idea is to make this an open data repository, where even during the research phase, collaborators that may have interesting methods for analyzing exome datasets come forth with those methodologies," Holden said. "Because many of the people that may have novel and creative and practical ways to do that may not have access to that data yet."

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