PMID- 28323125 OWN - NLM STAT- MEDLINE DCOM- 20180406 LR - 20240213 IS - 1600-0641 (Electronic) IS - 0168-8278 (Print) IS - 0168-8278 (Linking) VI - 67 IP - 1 DP - 2017 Jul TI - Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B *35:02 as a risk factor. PG - 137-144 LID - S0168-8278(17)30144-7 [pii] LID - 10.1016/j.jhep.2017.03.010 [doi] AB - BACKGROUND & AIMS: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. METHODS: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. RESULTS: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B *35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5x10(-8)). Verification of HLA-B *35:02 imputation was confirmed by sequence-based HLA typing. HLA-B *35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. CONCLUSION: HLA-B *35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. LAY SUMMARY: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B *35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward. CI - Copyright (c) 2017. Published by Elsevier B.V. FAU - Urban, Thomas Jacob AU - Urban TJ AD - Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA. FAU - Nicoletti, Paola AU - Nicoletti P AD - Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA. FAU - Chalasani, Naga AU - Chalasani N AD - Indiana University School of Medicine, Indianapolis, IN, USA. FAU - Serrano, Jose AU - Serrano J AD - National Institute of Diabetes Digestive and Kidney Diseases, Bethesda, MD, USA. FAU - Stolz, Andrew AU - Stolz A AD - University of Southern California, Los Angeles, CA, USA. FAU - Daly, Ann K AU - Daly AK AD - Newcastle University, Newcastle upon Tyne, United Kingdom. FAU - Aithal, Guruprasad P AU - Aithal GP AD - National Institute for Health Research Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham, United Kingdom. FAU - Dillon, John AU - Dillon J AD - University of Dundee, Dundee, United Kingdom. FAU - Navarro, Victor AU - Navarro V AD - Einstein Medical Center, Philadelphia, PA, USA. FAU - Odin, Joseph AU - Odin J AD - Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Barnhart, Huiman AU - Barnhart H AD - Duke University, Durham, NC, USA. FAU - Ostrov, David AU - Ostrov D AD - University of Florida College of Medicine, Gainesville, FL, USA. FAU - Long, Nanye AU - Long N AD - Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA. FAU - Cirulli, Elizabeth Trilby AU - Cirulli ET AD - Duke University, Durham, NC, USA. FAU - Watkins, Paul Brent AU - Watkins PB AD - Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA. FAU - Fontana, Robert John AU - Fontana RJ AD - University of Michigan, Ann Arbor, MI, USA. Electronic address: rfontana@med.umich.edu. CN - Drug-Induced Liver Injury Network (DILIN) CN - Pharmacogenetics of Drug-Induced Liver Injury group (DILIGEN) CN - International Serious Adverse Events Consortium (iSAEC) LA - eng GR - U01 DK065211/DK/NIDDK NIH HHS/United States GR - U01 DK083027/DK/NIDDK NIH HHS/United States GR - U01 DK065238/DK/NIDDK NIH HHS/United States GR - U01 DK065193/DK/NIDDK NIH HHS/United States GR - U01 DK065176/DK/NIDDK NIH HHS/United States GR - U01 DK083023/DK/NIDDK NIH HHS/United States GR - UL1 RR024982/RR/NCRR NIH HHS/United States GR - UL1 TR000083/TR/NCATS NIH HHS/United States GR - UL1 RR024150/RR/NCRR NIH HHS/United States GR - UL1 RR025761/RR/NCRR NIH HHS/United States GR - R21 DK089464/DK/NIDDK NIH HHS/United States GR - U01 DK083020/DK/NIDDK NIH HHS/United States GR - MR/N005953/1/MRC_/Medical Research Council/United Kingdom GR - U01 DK065201/DK/NIDDK NIH HHS/United States GR - U01 DK100928/DK/NIDDK NIH HHS/United States GR - UL1 RR024986/RR/NCRR NIH HHS/United States GR - U01 DK065184/DK/NIDDK NIH HHS/United States GR - UL1 RR024134/RR/NCRR NIH HHS/United States GR - U01 DK082992/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20170318 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Anti-Bacterial Agents) RN - 0 (HLA-B35 Antigen) RN - FYY3R43WGO (Minocycline) SB - IM MH - Adolescent MH - Adult MH - Alleles MH - Anti-Bacterial Agents/*adverse effects MH - Chemical and Drug Induced Liver Injury/*etiology MH - Female MH - Genome-Wide Association Study MH - HLA-B35 Antigen/*genetics MH - Humans MH - Male MH - Minocycline/*adverse effects MH - Risk Factors MH - Young Adult PMC - PMC5634615 MID - NIHMS871324 OTO - NOTNLM OT - Autoimmunity OT - Drug-induced liver injury OT - Genetic association OT - Human leukocyte antigen OT - Single nucleotide polymorphism COIS- Potential Conflicts of interest: Dr's Barnhart, Kleiner, Stolz, Urban, Long, Aithal, Daly, Dillon, Cirulli and Serrano have no conflicts of interest. Dr Watkins has served as a consultant to numerous pharmaceutical companies but none are involved in minocycline manufacturing or sales EDAT- 2017/03/23 06:00 MHDA- 2018/04/07 06:00 PMCR- 2017/10/10 CRDT- 2017/03/22 06:00 PHST- 2017/01/19 00:00 [received] PHST- 2017/03/02 00:00 [revised] PHST- 2017/03/04 00:00 [accepted] PHST- 2017/03/23 06:00 [pubmed] PHST- 2018/04/07 06:00 [medline] PHST- 2017/03/22 06:00 [entrez] PHST- 2017/10/10 00:00 [pmc-release] AID - S0168-8278(17)30144-7 [pii] AID - 10.1016/j.jhep.2017.03.010 [doi] PST - ppublish SO - J Hepatol. 2017 Jul;67(1):137-144. doi: 10.1016/j.jhep.2017.03.010. Epub 2017 Mar 18.