Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor.
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.



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.



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=2.5×10-8). 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.



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.



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.
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA.
Thomas Jacob
TJ
Urban
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
Paola
P
Nicoletti
Indiana University School of Medicine, Indianapolis, IN, USA.
Naga
N
Chalasani
National Institute of Diabetes Digestive and Kidney Diseases, Bethesda, MD, USA.
José
J
Serrano
University of Southern California, Los Angeles, CA, USA.
Andrew
A
Stolz
Newcastle University, Newcastle upon Tyne, United Kingdom.
Ann K
AK
Daly
National Institute for Health Research Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham, United Kingdom.
Guruprasad P
GP
Aithal
University of Dundee, Dundee, United Kingdom.
John
J
Dillon
Einstein Medical Center, Philadelphia, PA, USA.
Victor
V
Navarro
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Joseph
J
Odin
Duke University, Durham, NC, USA.
Huiman
H
Barnhart
University of Florida College of Medicine, Gainesville, FL, USA.
David
D
Ostrov
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA.
Nanye
N
Long
Duke University, Durham, NC, USA.
Elizabeth Trilby
ET
Cirulli
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA.
Paul Brent
PB
Watkins
University of Michigan, Ann Arbor, MI, USA. Electronic address: rfontana@med.umich.edu.
Robert John
RJ
Fontana
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D005260:Female; D055106:Genome-Wide Association Study; D015797:HLA-B35 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D008911:Minocycline / Q000009:adverse effects*; D012307:Risk Factors; D055815:Young Adult
D000900:Anti-Bacterial Agents; D015797:HLA-B35 Antigen; D008911:Minocycline
Autoimmunity; Drug-induced liver injury; Genetic association; Human leukocyte antigen; Single nucleotide polymorphism