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. 2017 Jul;67(1):137-144.
doi: 10.1016/j.jhep.2017.03.010. Epub 2017 Mar 18.

Minocycline Hepatotoxicity: Clinical Characterization and Identification of HLA-B∗35:02 as a Risk Factor

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Minocycline Hepatotoxicity: Clinical Characterization and Identification of HLA-B∗35:02 as a Risk Factor

Thomas Jacob Urban et al. J Hepatol. .
Free PMC article

Abstract

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=2.5×10-8). 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.

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.

Keywords: Autoimmunity; Drug-induced liver injury; Genetic association; Human leukocyte antigen; Single nucleotide polymorphism.

Conflict of interest statement

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

Figures

Figure 1
Figure 1. Manhattan plot showing genome-wide single variant association test results
The -log10(P value) from a logistic regression of each SNP on phenotype is plotted according to physical location of the SNPs on each of the 22 autosomes, with SNPs on different chromosomes colored with alternating colors. SNPs that exceeded a p-value of 10-5 threshold are marked in green color.
Figure 2
Figure 2. LocusZoom plot of association test results in the MHC region
The -log10(P value) from a logistic regression of each SNP as well as HLA-B*35:02 on phenotype is plotted according to physical locations in the MHC region. Linkage disequilibrium between each of the SNPs and the lead GWAS SNP (rs146765245) is indicated by color. Associations with the GWAS SNPs were not genome-wide significant, but imputation of HLA types revealed a genome-wide significant association with HLA-B*35:02. Local recombination rate in this region is also shown with the second Y-axis on the right. Several HLA genes with their direction of transcription are marked by arrows on the bottom and the locations of SNPs are marked by vertical bars on the top. This plot is generated using the web tool LocusZoom at http://locuszoom.sph.umich.edu/locuszoom/.
Figure 3
Figure 3. Molecular docking of minocycline in the HLA-B*35:02 antigen binding cleft
(a) A ribbon diagram of HLA-B*35:02 showing minocycline with white sticks for carbon, blue for nitrogen, red for oxygen, and white for hydrogen. Yellow dashes represent polar interactions between minocycline and HLA-B*35:02. (b). Minocycline is shown in the top scoring binding orientation predicted by molecular docking using AutoDock Vina. The molecular surface of HLA-B*35:02 is showing as violet for carbon, blue for nitrogen, red for oxygen, and white for hydrogen.

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