PMID- 32270503
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20221207
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 73
IP  - 1
DP  - 2021 Jan
TI  - Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With 
      Trimethoprim-Sulfamethoxazole Induced Liver Injury.
PG  - 268-281
LID - 10.1002/hep.31258 [doi]
AB  - BACKGROUND AND AIMS: Trimethoprim (TMP)-sulfamethoxazole (SMX) is an important 
      cause of idiosyncratic drug-induced liver injury (DILI), but its genetic risk 
      factors are not well understood. This study investigated the relationship between 
      variants in the human leukocyte antigen (HLA) class 1 and 2 genes and 
      well-characterized cases of TMP-SMX DILI. APPROACH AND RESULTS: European American 
      and African American persons with TMP-SMX DILI were compared with respective 
      population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, 
      San Diego, CA) for cases. The HLA genotype imputation with attribute bagging 
      program was used to impute HLA alleles for controls. The allele frequency 
      difference between case patients and controls was tested by Fisher's exact tests 
      for each ethnic group. For European Americans, multivariable logistic regression 
      with Firth penalization was used to test the HLA allelic effect after adjusting 
      for age and the top two principal components. Molecular docking was performed to 
      assess HLA binding with TMP and SMX. The European American subset had 51 case 
      patients and 12,156 controls, whereas the African American subset had 10 case 
      patients and 5,439 controls. Four HLA alleles were significantly associated in 
      the European American subset, with HLA-B*14:01 ranking at the top (odds ratio, 
      9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate 
      adjustment. All carriers of HLA-B*14:01 with TMP-SMX DILI possessed HLA-C*08:02, 
      another significant allele (P = 0.0026). This pattern was supported by 
      HLA-B*14:01-HLA-C*08:02 haplotype association (P = 1.33 x 10(-5) ). For the 
      African American patients, HLA-B*35:01 had 2.8-fold higher frequency in case 
      patients than in controls, with 5 of 10 patients carrying this allele. Molecular 
      docking showed cysteine at position 67 in HLA-B*14:01 and phenylalanine at 
      position 67 in HLA-B*35:01 to be the predictive binding sites for SMX 
      metabolites. CONCLUSIONS: HLA-B*14:01 is associated with TMP-SMX DILI in European 
      Americans, and HLA-B*35:01 may be a potential genetic risk factor for African 
      Americans.
CI  - (c) 2020 by the American Association for the Study of Liver Diseases.
FAU - Li, Yi-Ju
AU  - Li YJ
AUID- ORCID: 0000-0001-6996-4834
AD  - Department of Biostatistics and Bioinformatics, Duke University Medical Center, 
      Duke University, Durham, NC.
AD  - Molecular Physiology Institute, Duke University Medical Center, Duke University, 
      Durham, NC.
FAU - Phillips, Elizabeth J
AU  - Phillips EJ
AUID- ORCID: 0000-0002-7623-3383
AD  - Department of Medicine, Vanderbilt University Medical School and School of 
      Medicine Vanderbilt University, Nashville, TN.
FAU - Dellinger, Andrew
AU  - Dellinger A
AUID- ORCID: 0000-0003-1650-4329
AD  - Molecular Physiology Institute, Duke University Medical Center, Duke University, 
      Durham, NC.
FAU - Nicoletti, Paola
AU  - Nicoletti P
AD  - Department of Genetics and Genomic Science, Icahn School of Medicine at Mount 
      Sinai, Mount Sinai Health System, New York, NY.
FAU - Schutte, Ryan
AU  - Schutte R
AD  - Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, 
      University of Florida, Gainesville, FL.
FAU - Li, Danmeng
AU  - Li D
AD  - Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, 
      University of Florida, Gainesville, FL.
FAU - Ostrov, David A
AU  - Ostrov DA
AD  - Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, 
      University of Florida, Gainesville, FL.
FAU - Fontana, Robert J
AU  - Fontana RJ
AD  - Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
FAU - Watkins, Paul B
AU  - Watkins PB
AD  - Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of 
      Pharmacy, University of North Carolina, Chapel Hill, NC.
FAU - Stolz, Andrew
AU  - Stolz A
AD  - Division of Gastroenterology and Hepatology, Keck School of Medicine, University 
      of Southern California, Los Angeles, CA.
FAU - Daly, Ann K
AU  - Daly AK
AD  - Institute of Translational and Clinical Research, Newcastle University, Newcastle 
      Upon Tyne, United Kingdom.
FAU - Aithal, Guruprasad P
AU  - Aithal GP
AD  - Nottingham Digestive Diseases Centre, Nottingham University Hospital National 
      Health Service Trust and University of Nottingham, Nottingham, United Kingdom.
AD  - National Institute for Health Research Nottingham Biomedical Research Centre, 
      Nottingham University Hospital National Health Service Trust and University of 
      Nottingham, Nottingham, United Kingdom.
FAU - Barnhart, Huiman
AU  - Barnhart H
AD  - Department of Biostatistics and Bioinformatics, Duke University Medical Center, 
      Duke University, Durham, NC.
AD  - Clinical Research Institute, Duke University Medical Center, Duke University, 
      Durham, NC.
FAU - Chalasani, Naga
AU  - Chalasani N
AD  - Division of Gastroenterology and Hepatology, School of Medicine, Indiana 
      University, Indianapolis, IN.
CN  - Drug-induced Liver Injury Network
LA  - eng
GR  - U01 HG004438/HG/NHGRI NIH HHS/United States
GR  - U24 DK065176/DK/NIDDK NIH HHS/United States
GR  - U01 DK083027/DK/NIDDK NIH HHS/United States
GR  - U01 DK083020/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  - U01 AG006781/AG/NIA NIH HHS/United States
GR  - U01 HG004608/HG/NHGRI NIH HHS/United States
GR  - U01 DK065184/DK/NIDDK NIH HHS/United States
GR  - U01 DK082992/DK/NIDDK NIH HHS/United States
GR  - U01 DK065211/DK/NIDDK NIH HHS/United States
GR  - U01 HG007417/HG/NHGRI NIH HHS/United States
GR  - U01 DK065201/DK/NIDDK NIH HHS/United States
GR  - U01 HG004603/HG/NHGRI NIH HHS/United States
GR  - U01 DK100928/DK/NIDDK NIH HHS/United States
GR  - U01 HG004424/HG/NHGRI NIH HHS/United States
GR  - U01 DK065238/DK/NIDDK NIH HHS/United States
GR  - U01-DK065193/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (HLA-B Antigens)
RN  - 8064-90-2 (Trimethoprim, Sulfamethoxazole Drug Combination)
SB  - IM
MH  - Adult
MH  - Black or African American/genetics
MH  - Aged
MH  - Alleles
MH  - Chemical and Drug Induced Liver Injury/*etiology
MH  - Female
MH  - Genome-Wide Association Study
MH  - HLA-B Antigens/*genetics
MH  - Haplotypes
MH  - Humans
MH  - Logistic Models
MH  - Male
MH  - Middle Aged
MH  - Molecular Docking Simulation
MH  - Multivariate Analysis
MH  - Trimethoprim, Sulfamethoxazole Drug Combination/*adverse effects
MH  - White People/*genetics
PMC - PMC7544638
MID - NIHMS1590544
EDAT- 2020/04/10 06:00
MHDA- 2021/06/22 06:00
PMCR- 2022/01/01
CRDT- 2020/04/10 06:00
PHST- 2019/12/09 00:00 [received]
PHST- 2020/03/05 00:00 [revised]
PHST- 2020/03/12 00:00 [accepted]
PHST- 2020/04/10 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/04/10 06:00 [entrez]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.1002/hep.31258 [doi]
PST - ppublish
SO  - Hepatology. 2021 Jan;73(1):268-281. doi: 10.1002/hep.31258.