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

Li, Yi-Ju; Phillips, Elizabeth; Dellinger, Andrew; Nicoletti, Paola; Schutte, Ryan; Li, Danmeng; Ostrov, David A.; Fontana, Robert J.; Watkins, Paul B.; Stolz, Andrew; Daly, Ann K; Aithal, Guruprasad P.; Barnhart, Huiman; Chalasani, Naga; Drug?induced Liver Injury Network (DILIN)

Abstract

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 Cys67 in HLA?B*14:01 and Phe67 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.

• Journal Article Type: Article
• Acceptance Date: Apr 4, 2020
• Online Publication Date: Apr 9, 2020
• Publication Date: 2021-01
• Deposit Date: Apr 16, 2020
• Publicly Available Date: Apr 10, 2021
• Journal: Hepatology
• Print ISSN: 0270-9139
• Electronic ISSN: 1527-3350
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 73
• Issue: 1
• Pages: 268-281
• DOI: https://doi.org/10.1002/hep.31258
• Keywords: DILI, HLA, Haplotype, amino acid, Hepatotoxicity,
• Public URL: https://nottingham-repository.worktribe.com/output/4296945
• Publisher URL: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31258
• Additional Information: This is the peer reviewed version of the following article: Li, Y.?J., Phillips, E., 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. and (2020), HLA?B*14:01 and HLA?B*35:01 are associated with trimethoprim?sulfamethoxazole induced liver injury. Hepatology., which has been published in final form at https://doi.org/10.1002/hep.31258. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.