Study reveals first gene link to drug-induced liver damage
3 June 2009
Researchers from Newcastle University and colleagues have found that the genetic variant HLA-B*5701 is strongly linked to the likelihood of liver injury caused by the antibiotic flucloxacillin, which is widely used in Europe and Australia to treat staphylococcal infections. The results are published in 'Nature Genetics'.
There are many drugs that can cause liver injury in a small subset of patients, and this may lead to acute liver failure. Such events are rare and unpredictable, and although the exact mechanisms are unknown, research suggests a genetic contribution.
The International Serious Adverse Event Consortium is a non-profit research organisation exploring the impact genetics can have on how individuals respond to medicines. It aims to identify the DNA variants that could help predict the risk of serious adverse drug-related effects.
"Our aim is to ensure that commonly prescribed drugs can be used more safely," said Professor Ann Daly from Newcastle University, who led the study. "This study is an important step in developing a test that can be used prior to prescribing flucloxacillin."
The study looked at the genomes of 51 people affected by drug-induced liver injury. They found that individuals carrying at least one copy of the HLA-B*5701 gene variant were 80-100 times more likely than non-carriers to develop serious drug-induced liver injury in response to flucloxacillin. HLA-B is one of a number of highly variable genes responsible for immune function. The HLA-B*5701 variant is relatively common in Europe, but less prevalent in Africa and East Asia. The researchers also found other variations on chromosome 3 associated with increased risk of drug-induced liver injury.
The findings may help identify individuals who have an increased risk for flucloxacillin-related liver injury. However, despite being at substantially higher risk than non-carriers, only a small proportion of carriers actually develop liver problems after receiving the antibiotic. The researchers say further analysis and research will be needed to determine whether a test could be developed to predict susceptibility.
"We have assembled one of the largest DILI [drug-induced liver injury] research collections in the world and expect additional important genetic findings to emerge from these research efforts over the next 12-18 months," said Arthur Holden, founder and chairman of the Consortium.
"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."
Image: A hospital pharmacy. Credit: Wellcome Images
Reference
Daly AK et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 31 May 2009. [Epub ahead of print]