A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury

Abstract

Lumiracoxib is a selective cyclooxygenase-2 inhibitor developed for the symptomatic treatment of osteoarthritis and acute pain. Concerns over hepatotoxicity have contributed to the withdrawal or non-approval of lumiracoxib in most major drug markets worldwide. We performed a case-control genome-wide association study on 41 lumiracoxib-treated patients with liver injury (cases) and 176 matched lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 x 10(-10)). These findings were replicated in an independent set of 98 lumiracoxib-treated cases and 405 matched lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 x 10(-12)). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501-HLA-DQB1*0602-HLA-DRB5*0101-HLA-DQA1*0102, most significant allele P = 6.8 x 10(-25), allelic odds ratio = 5.0, 95% CI 3.6-7.0). 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.

Pharmacogenetics of nonsteroidal anti-inflammatory drugs

“…This aim can be reached through understanding the specific genomics of the patient and the NSAID. However, based upon some of the examples described throughout the article, there appears to be a considerable amount of research, such as retrospective studies modeled after Singer et al, 32 that must be completed to fully understand and ascertain the full mechanism of elimination that is employed when speaking of NSAIDs. These types of studies would help identify associations between genetic markers and adverse effects for patients.…”

“…It was a retrospective analysis utilizing a genome scan on 41 lumiracoxib-treated subjects with liver injury and 176 lumiracoxibtreated control subjects. 32 The analysis revealed a large number of SNPs from chromosome 6, showing an association with rs9270986 as the SNP with the lowest P-value (P ¼ 2.8 Â 10 À 10 ). A total of seven SNPs, exclusively mapped to the major histocompatability complex (MHC) class II region, maintained statistical significance following genome-wide multiple-testing correction.…”

“…32 This COX-2 inhibitor was developed for the treatment of osteoarthritis and acute pain. The trial utilized for the approval process was the Therapeutic Arthritis Research and Gastrointestinal Events Trial (TARGET).…”

“…63 Also, as previously noted, a genomic-wide study identified multiple SNPs from the MHC II region that revealed an association with the hepatotoxicity of lumiracoxib. 32 The hepatotoxicity is thought to be related to a HLA haplotype. The HLA-DQA1*0102 allele was identified as the most significant allele and a screening marker in lumiracoxib therapy.…”

“…64 In addition, many agents comprising mainstream pharmacotherapy would benefit marginally from widespread pharmacogenetics testing because of the cost of the agents. However, certain NSAIDs (foe example, lumiracoxib) may have been able to positively affect patient care with the use of prospective genomic testing to aid in the identification of patients who had a variation in the HLA-DQA1*0102 allele, 32 preventing hepatic impairment and possible hepatotoxicity.…”