AI Article Synopsis
- This study focuses on drug-induced liver injury (DILI) caused by amoxicillin-clavulanate (AC) and aims to find new risk factors along with creating a genetic risk score (GRS) to assess these risks.
- Researchers conducted genome-wide studies involving thousands of AC-DILI cases and population controls, discovering significant associations between AC-DILI risk and specific genetic markers such as ERAP2 and HLA-B∗15:18.
- The GRS, which includes various risk variants, was found to be a strong predictor of AC-DILI, enhancing existing clinical risk assessments for this condition.
Article Abstract
Background & Aims: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS).
Methods: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases.
Results: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model.
Conclusions: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9974860 | PMC |
| http://dx.doi.org/10.1053/j.gastro.2022.11.036 | DOI Listing |
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Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate.
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University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Article Synopsis
- This study focuses on drug-induced liver injury (DILI) caused by amoxicillin-clavulanate (AC) and aims to find new risk factors along with creating a genetic risk score (GRS) to assess these risks.
- Researchers conducted genome-wide studies involving thousands of AC-DILI cases and population controls, discovering significant associations between AC-DILI risk and specific genetic markers such as ERAP2 and HLA-B∗15:18.
- The GRS, which includes various risk variants, was found to be a strong predictor of AC-DILI, enhancing existing clinical risk assessments for this condition.
Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate-Induced Liver Injury in Spanish Patients.
Front Pharmacol
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Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd Málaga, Spain.
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View Article and Find Full Text PDFSusceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
Gastroenterology
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Facultad de Medicina, Hospital Universitario Virgen de la Victoria, Campus Universitario s/n, Málaga and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction.
Methods: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background.
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