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

JB Singer, S Lewitzky, E Leroy, F Yang, X Zhao… - Nature …, 2010 - nature.com
JB Singer, S Lewitzky, E Leroy, F Yang, X Zhao, L Klickstein, TM Wright, J Meyer
Nature genetics, 2010nature.com
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 …
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 × 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 × 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 × 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.
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