Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With Trimethoprim‐Sulfamethoxazole Induced Liver Injury

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.

An Updated Review of Genetic Associations With Severe Adverse Drug Reactions: Translation and Implementation of Pharmacogenomic Testing in Clinical Practice

“…Currently, Li et al identified that HLA-B*14:01 allele is the highest associated HLA with co-trimoxazole (sulfamethoxazole-trimethoprim)-related DILI in European Americans (OR = 9.2), while HLA-B*35:01 is the most associated allele in African Americans ( Li et al, 2021 ). In the recent research using the GWAS study, Nicoletti et al discovered that HLA-A*33:01 is associated with DILI, especially with terbinafine-induced liver injury (OR = 40.5) ( Nicoletti et al, 2017 ).…”

The Future of Personalized Medicine in Space: From Observations to Countermeasures

“…Trimethoprim-sulfamethoxazole (TMP-SMX) is an antibiotic available in the ISS formulary. Carriage of HLA-B*14:01 has been associated with TMP-SMX drug induced liver injury in European Americans and HLA-B*35:01 may be a risk factor for African Americans ( Li et al, 2021 ). Similarly, HLA-B*15:02, HLA-C*06:02 and HLA-C*08:01 have been associated with TMP-SMX-induced severe cutaneous reactions ( Kongpan et al, 2015 ).…”

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“…HLA-B*57:01 is the main risk factor for flucloxacillin-DILI and HLA-B*57:03 also show correlation ( Nicoletti et al, 2019 ). HLA-B*14:01 was associate with liver injury induced by cotrimoxazole ( Li et al, 2021 ), while HLA-B*35:02 increase the risk of the occurrence of DILI caused by minocycline ( Urban et al, 2017 ). Among antifungal drug, HLA-A*33:01 was significantly correlated with terbinafine induced DILI ( Nicoletti et al, 2017 ).…”