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

Thomas Jacob Urban; Paola Nicoletti; Naga P. Chalasani; José Serrano; Andrew Stolz; Ann K. Daly; Guruprasad P. Aithal; John Dillon; Victor Navarro; Joseph Odin; Huiman X. Barnhart; David Ostrov; Nanye Long; Elizabeth Trilby Cirulli; Paul Brent Watkins; Robert John Fontana

doi:10.1016/j.jhep.2017.03.010

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

Thomas Jacob Urban
, Paola Nicoletti
, Naga P. Chalasani
, José Serrano
, Andrew Stolz
, Ann K. Daly
, Guruprasad P. Aithal
, John Dillon
, Victor Navarro
, Joseph Odin
, Huiman X. Barnhart
, David Ostrov
, Nanye Long
, Elizabeth Trilby Cirulli
, Paul Brent Watkins
, Robert John Fontana

Research output: Contribution to journal › Article › peer-review

128 Citations (Scopus)

752 Downloads (Pure)

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 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.

Original language	English
Pages (from-to)	137-144
Number of pages	8
Journal	Journal of Hepatology
Volume	67
Issue number	1
Early online date	18 Mar 2017
DOIs	https://doi.org/10.1016/j.jhep.2017.03.010
Publication status	Published - Jul 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Autoimmunity
Drug-induced liver injury
Genetic association
Human leukocyte antigen
Single nucleotide polymorphism

ASJC Scopus subject areas

Hepatology

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10.1016/j.jhep.2017.03.010Licence: Elsevier User Licence

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© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Accepted author manuscript, 917 KBLicence: CC BY-NC-ND

Cite this

Urban, T. J., Nicoletti, P., Chalasani, N. P., Serrano, J., Stolz, A., Daly, A. K., Aithal, G. P., Dillon, J., Navarro, V., Odin, J., Barnhart, H. X., Ostrov, D., Long, N., Cirulli, E. T., Watkins, P. B., & Fontana, R. J. (2017). Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B*35:02 as a risk factor. Journal of Hepatology, 67(1), 137-144. https://doi.org/10.1016/j.jhep.2017.03.010

@article{18b82cfca7d64972821e54b05ed021eb,

title = "Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B*35:02 as a risk factor",

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 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.",

keywords = "Autoimmunity, Drug-induced liver injury, Genetic association, Human leukocyte antigen, Single nucleotide polymorphism",

author = "Urban, \{Thomas Jacob\} and Paola Nicoletti and Chalasani, \{Naga P.\} and Jos{\'e} Serrano and Andrew Stolz and Daly, \{Ann K.\} and Aithal, \{Guruprasad P.\} and John Dillon and Victor Navarro and Joseph Odin and Barnhart, \{Huiman X.\} and David Ostrov and Nanye Long and Cirulli, \{Elizabeth Trilby\} and Watkins, \{Paul Brent\} and Fontana, \{Robert John\}",

note = "The DILIN Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1TR000083 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and in part by the Intramural Research Program of the NIH, National Cancer Institute. This study was also supported in part by DK089464 (T.J.U).",

year = "2017",

month = jul,

doi = "10.1016/j.jhep.2017.03.010",

language = "English",

volume = "67",

pages = "137--144",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "1",

}

Urban, TJ, Nicoletti, P, Chalasani, NP, Serrano, J, Stolz, A, Daly, AK, Aithal, GP, Dillon, J, Navarro, V, Odin, J, Barnhart, HX, Ostrov, D, Long, N, Cirulli, ET, Watkins, PB & Fontana, RJ 2017, 'Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B*35:02 as a risk factor', Journal of Hepatology, vol. 67, no. 1, pp. 137-144. https://doi.org/10.1016/j.jhep.2017.03.010

TY - JOUR

T1 - Minocycline hepatotoxicity

T2 - Clinical characterization and identification of HLA-B*35:02 as a risk factor

AU - Urban, Thomas Jacob

AU - Nicoletti, Paola

AU - Chalasani, Naga P.

AU - Serrano, José

AU - Stolz, Andrew

AU - Daly, Ann K.

AU - Aithal, Guruprasad P.

AU - Dillon, John

AU - Navarro, Victor

AU - Odin, Joseph

AU - Barnhart, Huiman X.

AU - Ostrov, David

AU - Long, Nanye

AU - Cirulli, Elizabeth Trilby

AU - Watkins, Paul Brent

AU - Fontana, Robert John

N1 - The DILIN Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1TR000083 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and in part by the Intramural Research Program of the NIH, National Cancer Institute. This study was also supported in part by DK089464 (T.J.U).

PY - 2017/7

Y1 - 2017/7

N2 - 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 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.

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 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.

KW - Autoimmunity

KW - Drug-induced liver injury

KW - Genetic association

KW - Human leukocyte antigen

KW - Single nucleotide polymorphism

UR - https://www.scopus.com/pages/publications/85017498869

U2 - 10.1016/j.jhep.2017.03.010

DO - 10.1016/j.jhep.2017.03.010

M3 - Article

C2 - 28323125

SN - 0168-8278

VL - 67

SP - 137

EP - 144

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 1

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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Dillon, John

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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Fingerprint

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Dillon, John

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