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FDA and SAEC Link Gene Mutations to Liver Injury Associated with Antibiotic

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The US Food and Drug Administration and the International Serious Adverse Event Consortium have uncovered genetic associations between drug-induced liver injury and the antibiotic flucloxacillin.

Some people who receive flucloxacillin — a drug widely used in Europe and Australia, but not approved in the US — have variations in the HLA-B and HCP-5 genes, placing them at greater risk for drug-induced liver injury, according to the FDA.

Genome-wide and candidate gene studies, published in Nature Genetics on May 31 by researchers from institutions and companies involved in the SAEC, reported statistically significant associations between flucloxacillin-related liver injury and patients with variations in the major histocompatibility complex region, particularly rs2395029 in the HCP-5 gene and HLA-B*5701. In HLA-B*5701 carriers, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance.

"Although the exact mechanism of [drug-induced liver injury] is unknown, research suggests that a person's genes contribute to their likelihood of developing the injury," the FDA and the SAEC said in a statement announcing their finding.

A small subset of patients receiving flucloxacillin is affected in this manner; but in this group drug-induced liver failure may lead to acute liver failure in certain patients.

The SAEC, established in October 2007, is a non-profit entity comprising large pharmaceutical companies, research organizations, and regulatory bodies. The FDA guides the consortium with scientific and strategic input. The first two projects of the consortium focused on uncovering the genetic underpinning of drug-related liver toxicity and the rare skin condition Stevens-Johnson Syndrome.

Earlier this year, the SAEC released genetic risk data associated with Stevens-Johnson Syndrome [see PGx Reporter 02-18-2009].

Now, with these new findings published on drug-induced liver injury, "the research community will have better tools to evaluate predictive biomarkers for adverse events," Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, said in a statement. "This type of collaborative research will eventually reduce a patient's likelihood of experiencing serious, and sometimes life-threatening, adverse drug events."

HLA-B*5701 has been previously linked to adverse drug reactions in those taking the HIV drug abacavir [see PGx Reporter 06-30-2008].

Qiagen and Delphic Laboratories offer HLA-B*5701 testing in European countries for hypersensitivity to abacavir.

Although these existing tests could "possibly" be used to detect liver toxicity linked to HLA-B*5701, ultimately companion diagnostics for flucloxacillin-related liver injury would need to interrogate multiple biomarkers with greater sensitivity and specificity, said Arthur Holden, founder and chairman of the SAEC.

Study and Associations

The team used genome-wide and candidate gene association studies to identify variants linked to liver injury in 51 individuals of northern European descent who had had liver injury while on flucloxacillin. Researchers also evaluated 282 sex- and ancestry-matched controls for 1,072,820 SNPs and CNVs using the Illumina Human 1M-Duo BeadChip.

Expression Analysis conducted the genotyping for the study at its facility in North Carolina.

A SNP on chromosome 6 called rs2395029 provided the strongest association with flucloxacillin-related liver injury. However, researchers suspect that rs2395029, which falls in a gene called HCP5, is not actually the culprit, but HLA-B*5701 is.

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Lead author Ann Daly, a pharmacogenetics researcher at Newcastle University, told Pharmacogenomics Reporter sister publication GenomeWeb Daily News that HLA-B*5701 is in complete linkage disequilibrium with rs2395029.

Direct HLA-B*5701 genotyping revealed perfect correlation between the presence of rs2395029 and HLA-B*5701. As a result, the research team concluded that like rs2395029, HLA-B*5701 was significantly associated with flucloxacillin-related liver damage.

According to the authors, roughly five percent of European individuals carry the rs2395029 risk allele. However, in the study population who had drug-induced liver toxicity, approximately 84 percent carried the allele. According to epidemiological surveys done in the past, roughly one in every 10,000 patients receiving flucloxacillin experiences liver-related adverse reactions.

The SAEC's research was done in collaboration with a larger UK-based drug-induced liver injury study, called Diligen. Daly and her colleagues tapped into a UK network that was developed four years ago to identify individuals who had experienced liver injury related to flucloxacillin. In the network, the average age of those experiencing liver toxicity was about 63 years old and liver-related adverse effects were more common in women than in men.

Impact in the US?

Flucloxacillin — a drug marketed by CSL Limited under the brand name Flopen and by GlaxoSmithKline under the name Floxapen — is a penicillin-derived beta lactam antibiotic commonly prescribed in the UK, Europe, and Australia to treat staphylococcal infections and infections caused by other gram-positive bacteria. GSK is a member of the SAEC consortium.

In the markets where flucloxacillin is available, if this new research eventually inspires regulatory authorities to recommend genetic testing prior to administration of the drug, it could in effect lead to the development of new diagnostic testing market.

Since flucloxacillin is not approved in the US, the genetic link uncovered by the SAEC has no immediate impact here. However, this could change once the SAEC completes genome-wide studies looking at the genetic risk of drug induced liver injury associated with other drugs.

"At this point, the conclusions only pertain to flucloxacillin. We are currently completing GWAS analyses on additional drugs where we have adequate numbers of drug-induced liver injury cases and population-matched controls," SAEC's Holden told Pharmacogenomics Reporter this week.

The consortium plans to report this additional data by the end of the year.

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