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

Nature Genetics volume 42, pages 711–714 (2010)Cite this article

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Abstract

Lumiracoxib is a selective cyclooxygenase-2 inhibitor developed for the symptomatic treatment of osteoarthritis and acute pain1. 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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Figure 1
Figure 2: Cumulative Kaplan-Meier incidence estimates (shown as percentages) for liver enzyme elevations in the TARGET study comparing HLA-DQA1*0102 carrier status and comparator arms.

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Acknowledgements

The authors thank C. Hurwitz, J. Decker, G. Yarbrough, J. Somers, C. Wache-Mainier, M. Waldvogel and N. Hartmann for the help in genotyping the samples; S. Stavar for assistance with data management and Y. He and R. Yelensky for helpful discussions; P. Vancutsem for input into the project; and all the patients who participated in the TARGET study and all the investigators of the TARGET study group.

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  1. Jonathan B Singer and Steve Lewitzky: These authors contributed equally to this work.

Authors and Affiliations

  1. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA

    Jonathan B Singer, Steve Lewitzky, Elisabeth Leroy, Fan Yang, Xiaojun Zhao, Lloyd Klickstein, Timothy M Wright, Joanne Meyer & Charles A Paulding

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  1. Jonathan B Singer
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Contributions

The genome-wide association study was designed by C.A.P., S.L., J.M. and J.B.S. with analysis and interpretation performed by C.A.P., S.L., J.B.S., J.M. and F.Y. The HLA fine mapping study was designed by C.A.P., J.B.S. and S.L., and analysis and interpretation was performed by C.A.P., J.B.S., S.L., J.M., L.K. and T.M.W. Genotyping was supervised and performed by E.L. and X.Z. C.A.P., S.L. and J.B.S. wrote the first draft of the manuscript, and all other authors contributed to and approved the final draft.

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Correspondence to Charles A Paulding.

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All authors are employees and stockholders of Novartis.

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Supplementary Tables 1–6, Supplementary Figures 1–5 and Supplementary Note (PDF 493 kb)

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Singer, J., Lewitzky, S., Leroy, E. et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 42, 711–714 (2010). https://doi.org/10.1038/ng.632

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