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Publication Information
Affiliation
1Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University, Durham, NC.
2Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, NC.
3Department of Medicine, Vanderbilt University Medical School and School of Medicine Vanderbilt University, Nashville, TN.
4Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY.
5Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
6Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
7Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
8Division of Gastroenterology and Hepatology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
9Institute of Translational and Clinical Research, Newcastle University, Newcastle Upon Tyne, United Kingdom.
10Nottingham Digestive Diseases Centre, Nottingham University Hospital National Health Service Trust and University of Nottingham, Nottingham, United Kingdom.
11National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospital National Health Service Trust and University of Nottingham, Nottingham, United Kingdom.
12Clinical Research Institute, Duke University Medical Center, Duke University, Durham, NC.
13Division of Gastroenterology and Hepatology, School of Medicine, Indiana University, Indianapolis, IN.
Authors
Aithal GP, Barnhart H, Chalasani N, Daly AK, Dellinger A, Fontana RJ, Li D, Li YJ, Nicoletti P, Ostrov DA, Phillips E, Schutte R, Stolz A, Watkins PB
Studies
Abstract
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.