Human leukocyte antigen B∗14:01 and B∗35:01 are associated with trimethoprim-sulfamethoxazole induced liver injury
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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 × 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.
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Previous work found that human leukocyte antigen (HLA) B*14:01 and HLA-B*35:01 were associated with SMX-TMP liver injury for European Americans and African Americans, respectively.
“Previous work has explored risk factors for SMX-induced DILI and found that human leukocyte antigen (HLA) B*14:01 and HLA-B*35:01 were associated with SMX-TMP liver injury for European Americans and African Americans, respectively.29”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [29]
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- Authors
- Li, Y., Phillips, E. J., Dellinger, A., Nicoletti, P., Schutte, R., Li, D., Ostrov, D. A., Fontana, R. J., Watkins, P. B., Stolz, A., Daly, A. K., Aithal, G. P., Barnhart, H., Chalasani, N., & the Drug‐induced Liver Injury Network
- Affiliations
- Duke University (US)
- Vanderbilt University (US)
- Mount Sinai Health System (US)
- University of Florida (US)
- University of Michigan (US)
- University of North Carolina at Chapel Hill (US)
- University of Southern California (US)
- Newcastle University (GB)
- National Health Service (GB)
- Corresponding author
- Chalasani, Naga
- ORCID
- Venue
- Hepatology
- Published
- 2021-01
- Volume
- 73
- Issue
- 1
- Pages
- 268-281
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC7544638
- OpenAlex
- W3015665353
- Cited by
- 76
- References
- 33
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 8 · 2023: 14 · 2022: 14 · 2021: 11 · 2020: 4
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- UNC Libraries
- Funders
- Mayo Clinic
- Andrea and Charles Bronfman Philanthropies
- Vanderbilt University (U01HG04603)
- University of Pennsylvania (U01-DK100928)
- Northwestern University
- Johns Hopkins University (U01HG004438)
- University of Texas Southwestern Medical Center (U01-DK083027, U01-DK083020, U01-DK082992, U01-DK100928)
- Broad Institute (U01HG004424)
- National Institutes of Health (5u01dk065211-22, 5u01dk065238-11, 5u01dk065193-05, 5u01dk065184-22, U01-DK065211, U24-DK065176)
- University of California, San Francisco
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Aging (U01AG006781)
- National Human Genome Research Institute (U01 HG04603, UOIHG004599, U01HG007417, U01HG004424, U01HG004608, U01HG004438, U01HG004603)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01 DK-065238, U01‐DK065193, U01 DK-065184, DK065211, DK100928, DK082992, DK 065193, U24DK065176, U01DK083023, DK065184, U01 DK-065211, U01DK082992, DK065176, DK083020, DK065238, DK083023, U01DK100928, DK 065201, DK083027, U01DK083027, U01DK065201, U01DK083020, U01DK065176)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- trimethoprim-sulfamethoxazole, drug-induced liver injury, HLA-B*35:01, HLA allele frequencies, genetic susceptibility, HLA-peptide binding, molecular docking, European Americans, African Americans, idiosyncratic drug toxicity
- MeSH terms
- Adult, Aged, Alleles, Black or African American, Female, Haplotypes, Humans, Male, Middle Aged, HLA-B Antigens, Trimethoprim, Sulfamethoxazole Drug Combination, Multivariate Analysis, Logistic Models, White People, Genome-Wide Association Study, Chemical and Drug Induced Liver Injury, Molecular Docking Simulation
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