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Team IDs Risk Variants for Liver Damage Following Antibiotic Use

NEW YORK (GenomeWeb News) – A team of researchers from the UK and US identified genetic variants associated with increased risk of liver damage for individuals taking the antibiotic flucloxacillin.

The team used a combination of genome-wide and candidate gene association studies to find variants linked to adverse liver response in individuals taking flucloxacillin. The work, which appeared online yesterday in Nature Genetics, suggests HLA-B*5701 — an allele previously implicated in adverse reactions to an HIV drug called abacavir — may predispose individuals to a higher risk of liver injury while taking flucloxacillin.

Based on these results, the team is generating new hypotheses about the mechanism of this liver damage, suggesting immune function may be involved.

Flucloxacillin 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. The pharmaceutical company CSL Limited markets flucloxacillin under the trade name Flopen, while GlaxoSmithKline sells it under the trade name Floxapen.

Previous epidemiological surveys suggest roughly one in every 10,000 patients receiving flucloxacillin experiences liver-related adverse reactions, lead author Ann Daly, a pharmacogenetics researcher at Newcastle University, told GenomeWeb Daily News.

For the GWAS arm of the study, the team evaluated 51 individuals of northern European descent who had experienced drug-induced liver injury while taking flucloxacillin and 282 sex and ancestry matched controls at 1,072,820 SNPs and CNVs using the Illumina Human 1M-Duo BeadChip. Genotyping for the study was done at Expression Analysis in North Carolina.

The research was done as part of the Diligen study, a UK-based effort to identify genetic and other factors contributing to drug-induced liver toxicity. Daly and her colleagues tapped into a UK network that was developed about four years ago to identify individuals who had experienced liver injury related to flucloxacillin. 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.

After tossing out more than 200,000 markers that didn't meet their quality control specifications, the team tested for associations with flucloxacillin-related liver injury. The strongest association they identified was with a SNP on chromosome 6 called rs2395029, which falls in a gene called HCP5. The same SNP, which is near the major histocompatibility complex or MHC region, has been previously shown to decrease HIV1 viral set point.

The team found that roughly five percent of European individuals tested carried the risk allele. But among the 51 individuals who'd had drug-induced liver toxicity the frequency was much higher: about 84 percent of the cases tested carried the risk allele.

Even so, the researchers suspect that it's not actually rs2395029 that is behind the flucloxacillin-related liver injury, Daly said, but an allele called HLA-B*5701, which is in complete linkage disequilibrium with rs2395029. HLA-B*5701 has been previously linked to adverse drug reactions in those taking abacavir.

Direct HLA-B*5701 genotyping revealed perfect correlation between the presence of rs2395029 and HLA-B*5701. As expected from these results, the team reported that, like rs2395029, HLA-B*5701 was significantly associated with flucloxacillin-related liver damage.

Candidate gene typing experiments also uncovered potential associations with other loci, such as the MHC gene HLA-DRB1 and the tumor necrosis factor gene TNF-alpha — also implicated in abacavir sensitivity.

The team confirmed these findings in a follow-up study involving 23 individuals who'd had liver injury while taking flucloxacillin alone or in combination with another drug. They also tested 64 control individuals who'd taken flucloxacillin but didn't show symptoms of liver injury.

Because relatively few individuals — just one in every 500 or 1,000 — who carry the HLA-B*5701 allele develop liver problems while taking flucloxacillin, the authors noted, prospective genetic testing for drug-induced liver injury based on HLA-B*5701 would likely have a high false positive rate.

Nevertheless, the study and others like it may offer clues about the mechanism behind liver damage in some individuals taking flucloxacillin. Based on their results so far, Daly and her team believe such liver problems may be related to a T-cell immune response. In particular, Daly said, they suspect the antibiotic or one of its metabolites may bind to liver proteins, creating a complex that the immune system perceives as foreign and attacks.

The observation that women are more likely than men to experience liver injury while taking flucloxacillin may also fit this theory: Daly noted that women tend to be more prone to autoimmune disorders.

The researchers are currently starting to test this hypothesis by looking at how T-cells isolated from individuals who carry the HLA-B*5701 allele respond to flucloxacillin in the lab. They are also conducting another GWAS with Expression Analysis to look for additional variants explaining liver damage caused by flucloxacillin as well as other drugs.

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