HLA‐B*14:01 and HLA‐B*35:01 are associated with trimethoprim‐sulfamethoxazole induced liver injury

BACKGROUND AND AIM: Trimethoprim-sulfamethoxazole (TMP-SMX) is an important cause of idiosyncratic drug induced liver injury (DILI), but its genetic risk factors are not well understood. We investigated the relationship between variants in the HLA Class I and II genes and well characterized cases of TMP-SMX DILI. METHODS: European American and African American persons with TMP-SMX DILI were compared to respective population controls. HLA sequencing was performed by Illumina MiSeq for cases. HLA genotype imputation with attribute bagging (HIBAG) program was used to impute HLA alleles for controls. Allele frequency difference between cases and controls was tested by Fisher exact tests per ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess the HLA binding with TMP and SMX. RESULTS: The European American subset had 51 cases and 12,156 controls, while the African American subset had 10 cases and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA-B*14:01 ranking at the top (OR: 9.20, 95% CI: 3.16-22.35, p=0.0003) after covariate adjustment. All HLA-B*14:01 carriers 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=1.33x10(-5) ). For the African Americans, HLA-B*35:01 had 2.8-fold higher frequency in cases than in controls, with five of 10 patients carrying this allele. Molecular docking showed Cys(67) in HLA-B*14:01 and Phe(67) in HLA-B*35:01 to be the predictive binding sites to SMX metabolites. CONCLUSION: 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.