June 1, 2009
Research Designed To Discover Genetic Markers
The International Serious Adverse Events Consortium (SAEC) announced today initial results from its research designed to discover genetic markers that may predict individuals at risk for serious drug induced liver injury (DILI). The SAEC is a nonprofit research corporation, launched in the fall of 2007, comprised of and funded by 10 leading pharmaceutical companies and the Wellcome Trust. The U.S. Food and Drug Administration (FDA) also contributes to the scientific and strategic direction of this novel research effort. The collection and initial characterization of the DILI cases supporting these results was performed by the UK-based DILIGEN network, led by Professor Ann Daly and colleagues at Newcastle University, but also involving researchers at the University of Liverpool and at Queen's Medical Centre, Nottingham.
Patients respond differently to medicines, and all medicines can have adverse effects in some people. The SAEC's work is based on the hypothesis that many of these differences have a genetic basis. Its research studies are exploring the impact genetics can have on how individuals respond to medicines. There are a large number of drugs that can cause liver injury in a very small subset of patients, and in rare cases this may lead to acute liver failure. Although the exact mechanisms behind such rare and unpredictable DILI is unknown, research suggests a genetic contribution.
In a Nature Genetics paper published on May 31, the SAEC and Newcastle University's analysis of a subset of DNA patients has led to the discovery that HLA-B*5701 is a major determinant of liver injury induced by flucloxacillin. Flucloxacillin is an antibiotic widely used in Europe and Australia, mainly in the treatment of staphylococcal infections. HLA-B is one of a number of highly variable genes responsible for immune function. The study found that individuals carrying at least one copy of HLA-B*5701 were 80-100 times more likely than non-carriers to develop DILI in response to this antibiotic. This risk-associated variant is relatively common in Europe, but less prevalent in Africa and East Asia. In addition to HLA-B*5701, variations on chromosome 3 were also found to influence the risk for DILI. These findings provide initial insights into the mechanism of DILI and may have the potential to help identify individuals who have an increased risk for flucloxacillin related liver injury. Despite being at substantially higher risk than non-carriers, only a small proportion of carriers actually develop liver problems in response to flucloxacillin. Thus, further analysis and research will be needed to determine whether a clinically useful biomarker test could be developed for this susceptibility.
The paper can be found on both the Nature Genetics (http://www.nature.com/ng/index.htm) and the SAEC's (www.saeconsortium.org) websites. Qualified researchers, who enter into a data use agreement, can obtain free access via the SAEC's website to the supporting study data, for use exclusively in biomedical research.
"We are pleased to be able to provide these initial results to the research community, to both improve the productivity of drug development and to begin the critical process of developing validated biomarkers to forecast patients who may be at risk for DILI," said Arthur Holden, founder and chairman of the SAEC. "To date, in conjunction with our collaborators, we have assembled one of the largest DILI research collections in the world. We expect additional important DILI genetic findings to emerge from these research efforts over the next 12-18 months."
"Our aim is to ensure that commonly prescribed drugs can be used more safely. This is an important step in developing a test that can be used prior to prescribing flucloxacillin. We look forward to making further progress in the area of DILI research with our international collaborators" said Ann Daly, Professor of Pharmacogenetics at Newcastle University who leads the DILIGEN network.
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International Serious Adverse Events Consortium