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Novartis Study Detects Drug-Related Liver Injury Risk Variants

This article has been updated to correct the drug's potential brandname in the EU.

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A genome-wide association study by Novartis researchers has identified genetic variants linked to liver injury in some individuals taking the anti-inflammatory drug lumiracoxib.

A team of investigators from the Novartis Institutes for BioMedical Research did a case-control GWAS involving dozens of individuals who had experienced liver injury after taking lumiracoxib and nearly 200 control individuals who had taken the drug without experiencing liver damage. The study, appearing in the early, online edition of Nature Genetics this week, identified lumiracoxib-associated liver injury risk SNPs in the major histocompatibility complex (MHC) class II region.

Based on their findings so far, those involved in the study say it may be possible to develop genetic tests to find those at risk of liver-related complications prior to prescribing lumiracoxib. The drug was submitted under the brand name Joicela in December 2009 for marketing authorization in the European Union for the treatment of signs and symptoms of osteoarthritis, in combination with a genetic biomarker.

"These results offer the potential to improve the safety profile of lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from lumiracoxib treatment," senior author Charles Paulding, senior group head of pharmacogenetic analysis at the Novartis Institutes for BioMedical Research, and his colleagues wrote.

Drug-induced liver injury is a rare but serious side effect seen in a subset of individuals taking certain drugs, including the selective cyclooxygenase-2 (Cox-2) inhibitor lumiracoxib, which was designed for treating osteoarthritis and acute pain.

Consequently, the researchers explained, lumiracoxib has not obtained regulatory approval in some markets and has been withdrawn from others. But, they added, finding ways to distinguish individuals at risk of liver injury prior to treatment should make it possible to safely use lumiracoxib and similar treatments.

"The discovery of genetic markers able to identify individuals at risk for developing [drug-induced liver injury] could potentially make otherwise safe and efficacious drugs available for use," they wrote.

To explore this possibility, Paulding and his co-workers used the Affymetrix Genome-Wide Human SNP 6.0 array to genotype 41 individuals with lumiracoxib-related liver injury and 176 matched controls who had taken the drug but did not have liver injury.

DNA for the work was collected through an international study of osteoarthritis patients taking lumiracoxib, naproxen, or ibuprofen called the Therapeutic Arthritis Research and Gastrointestinal Event Trial, or TARGET.

When they compared genotype data from the cases and controls, the team found seven liver injury associated SNPs in a region of the genome coding the MHC class II — a set of immune genes that include human leukocyte antigen (HLA) genes. They subsequently verified these findings by testing another 98 cases and 405 controls.

"The mapping of the genetic association to the MHC class II region suggests a possible immunological mechanism for lumiracoxib-related hepatotoxicity," they wrote, noting that previous studies have also linked MHC genes to other adverse drug effects such as hyper-sensitivity to the HIV drug abacavir and liver injury associated with the antibiotic flucloxacillin.

The team subsequently did fine mapping of several HLA genes in this region using a One Lambda LABType DNA typing kit combined with Luminex xMAP multiplexing tools or Sanger sequencing, turning up four alleles in a shared HLA haplotype that were significantly associated with lumiracoxib-associated liver injury.

When they genotyped one allele in particular, HLA-DQA1*0102, in DNA from 4,518 TARGET participants, the researchers found evidence that individuals carrying the allele have a much higher risk of liver injury — particularly after several weeks or months of taking lumiracoxib.

Because HLA-DQA1*0102 turned up in roughly a third of TARGET participants, the team noted, testing for the allele prior to lumiracoxib use would likely screen out more individuals than are actually at risk of liver injury. Even so, they explained, such screening "would result in a substantial reduction in risk for those patients eligible to receive lumiracoxib."

"In addition to providing insight into the mechanisms of lumiracoxib-related hepatotoxicity, these findings offer the potential to improve the safety profile of lumiracoxib and move the field of personalized medicine forward with one of the first marketed [drug-induced liver injury] safety markers," the researchers concluded.

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