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 DILI in a well-phenotyped cohort of patients. Methods: Caucasian patients with minocycline DILI underwent genome-wide...
| Main Authors: | , , , , , , , , , , , , , , , |
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Elsevier
2017
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| Online Access: | https://eprints.nottingham.ac.uk/41683/ |
| _version_ | 1848796330014539776 |
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| author | Urban, Thomas Jacob Nicoletti, Paola Chalasani, Naga Serrano, Jose Stolz, Andrew Daly, Ann K. Aithal, Guruprasad P. Dillon, John F. Navarro, Victor Odin, Joseph Barnhart, Huiman X. Ostrov, David Long, Nanye Cirulli, Elizabeth Theresa Watkins, Paul Brent Fontana, Robert John |
| author_facet | Urban, Thomas Jacob Nicoletti, Paola Chalasani, Naga Serrano, Jose Stolz, Andrew Daly, Ann K. Aithal, Guruprasad P. Dillon, John F. Navarro, Victor Odin, Joseph Barnhart, Huiman X. Ostrov, David Long, Nanye Cirulli, Elizabeth Theresa Watkins, Paul Brent Fontana, Robert John |
| author_sort | Urban, Thomas Jacob |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline 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: Amongst the 25 cases, 80% were female, median age was 19 years and median latency from drug start to DILI onset was 318 days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1077 U/L (range: 63 to 2333), median bilirubin 4.5 mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no subjects 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 x 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. |
| first_indexed | 2025-11-14T19:46:16Z |
| format | Article |
| id | nottingham-41683 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:46:16Z |
| publishDate | 2017 |
| publisher | Elsevier |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-416832020-05-04T18:38:19Z https://eprints.nottingham.ac.uk/41683/ Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor Urban, Thomas Jacob Nicoletti, Paola Chalasani, Naga Serrano, Jose Stolz, Andrew Daly, Ann K. Aithal, Guruprasad P. Dillon, John F. Navarro, Victor Odin, Joseph Barnhart, Huiman X. Ostrov, David Long, Nanye Cirulli, Elizabeth Theresa Watkins, Paul Brent Fontana, Robert John Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline 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: Amongst the 25 cases, 80% were female, median age was 19 years and median latency from drug start to DILI onset was 318 days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1077 U/L (range: 63 to 2333), median bilirubin 4.5 mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no subjects 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 x 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. Elsevier 2017-03-18 Article PeerReviewed Urban, Thomas Jacob, Nicoletti, Paola, Chalasani, Naga, Serrano, Jose, Stolz, Andrew, Daly, Ann K., Aithal, Guruprasad P., Dillon, John F., Navarro, Victor, Odin, Joseph, Barnhart, Huiman X., Ostrov, David, Long, Nanye, Cirulli, Elizabeth Theresa, Watkins, Paul Brent and Fontana, Robert John (2017) Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor. Journal of Hepatology . ISSN 1600-0641 Drug induced liver injury Single nucleotide polymorphism Genetic association Autoimmunity Human leukocyte antigen https://doi.org/10.1016/j.jhep.2017.03.010 doi:10.1016/j.jhep.2017.03.010 doi:10.1016/j.jhep.2017.03.010 |
| spellingShingle | Drug induced liver injury Single nucleotide polymorphism Genetic association Autoimmunity Human leukocyte antigen Urban, Thomas Jacob Nicoletti, Paola Chalasani, Naga Serrano, Jose Stolz, Andrew Daly, Ann K. Aithal, Guruprasad P. Dillon, John F. Navarro, Victor Odin, Joseph Barnhart, Huiman X. Ostrov, David Long, Nanye Cirulli, Elizabeth Theresa Watkins, Paul Brent Fontana, Robert John Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor |
| title | Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor |
| title_full | Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor |
| title_fullStr | Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor |
| title_full_unstemmed | Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor |
| title_short | Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor |
| title_sort | minocycline hepatotoxicity: clinical characterization and identification of hla-b∗ 35:02 as a risk factor |
| topic | Drug induced liver injury Single nucleotide polymorphism Genetic association Autoimmunity Human leukocyte antigen |
| url | https://eprints.nottingham.ac.uk/41683/ https://eprints.nottingham.ac.uk/41683/ https://eprints.nottingham.ac.uk/41683/ |