HLA associations with infliximab-induced liver injury

Bruno, Christopher D.; Fremd, Brandon; Church, Rachel J.; Daly, Ann K.; Aithal, Guruprasad P.; Bjornsson, Einar S.; Larrey, Dominique; Watkins, Paul B.; Chow, Christina R.

Abstract

Biomarkers that are able to identify patients at risk of drug-induced liver injury (DILI) after treatment with infliximab could be important in increasing the safety of infliximab use. We performed a genetic analysis to identify possible human leukocyte antigen (HLA) associations with drug-induced liver injury in European Caucasian users of infliximab in a retrospective study of 16 infliximab-DILI patients and 60 matched controls. In infliximab-associated liver injury, multiple potentially causal individual HLA associations were observed, as well as possible haplotypes. The strongest associated HLA allele was HLA-B*39:01 (P=0.001; odds ratio [OR] 43.6; 95% confidence interval [CI] 2.8-infinity), which always appeared with another associated allele C*12:03 (P=0.032; OR 6.1; 95% CI 0.9-47.4). Other associations were observed with HLAs DQB1*02:01 (P=0.007; OR 5.7; 95% CI 1.4-24.8), DRB1*03:01 (P=0.012; OR 4.9; 95% CI 1.2-20.5), and B*08:01 (P=0.048; OR 3.4; 95% CI 0.9-13.2), which also appeared together whenever present in cases. Additional associations were found with HLA-DPB1*10:01 (P=0.042; OR 20.9; 95% CI 0.7-infinity) and HLA-DRB1*04:04 (P=0.042; OR 20.9; 95% CI 0.7-infinity). A strong association with HLA-B*39:01 was identified as a potentially causal risk factor for infliximab-induced DILI. Future work should aim to validate this finding and explore possible mechanisms through which the biologic interacts with this particular allele.

Citation

Bruno, C. D., Fremd, B., Church, R. J., Daly, A. K., Aithal, G. P., Bjornsson, E. S., Larrey, D., Watkins, P. B., & Chow, C. R. (2020). HLA associations with infliximab-induced liver injury. Pharmacogenomics Journal, 20, 681–686. https://doi.org/10.1038/s41397-020-0159-0

• Journal Article Type: Article
• Acceptance Date: Jan 27, 2020
• Online Publication Date: Feb 6, 2020
• Publication Date: 2020-10
• Deposit Date: Feb 3, 2020
• Publicly Available Date: Aug 7, 2020
• Journal: The Pharmacogenomics Journal
• Print ISSN: 1470-269X
• Electronic ISSN: 1473-1150
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Pages: 681–686
• DOI: https://doi.org/10.1038/s41397-020-0159-0
• Keywords: Molecular Medicine; Genetics; Pharmacology
• Public URL: https://nottingham-repository.worktribe.com/output/3868173
• Publisher URL: https://www.nature.com/articles/s41397-020-0159-0
• Additional Information: Received: 13 November 2019; Revised: 22 January 2020; Accepted: 27 January 2020; First Online: 6 February 2020; : ; : CDB, BF, and CRC are employees of Emerald Lake Safety. GPA is supported by the NIHR Nottingham Biomedical Research Centre. AKD has received funding from the International Serious Adverse Events Consortium for iDILIC recruitment. RJC, ESB, DL, and PBW have no conflicts to declare.