Paola Nicoletti1, Anneke N Werk, Ashley Sawle, Yufeng Shen, Thomas J Urban, Sally A Coulthard, Einar S Bjornsson, Ingolf Cascorbi, Aris Floratos, Thomas Stammschulte, Ursula Gundert-Remy, Matthew R Nelson, Guruprasad P Aithal, Ann K Daly. 1. Departments of aSystems Biology bBiomedical Informatics cThe Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York dUNC Eshelman School of Pharmacy, Chapel Hill, North Carolina eTarget Sciences, GSK, King of Prussia, Pennsylvania, USA fInstitute for Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel gDrug Commission of the German Medical Association (DCGMA), Berlin, Germany hInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne iNational Institute for Health Research (NIHR), Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK jDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The National University Hospital of Iceland, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Abstract
OBJECTIVE: Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown. MATERIALS AND METHODS: Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10,588 population controls. DILI was diagnosed by causality assessment and expert review. Human leucocyte antigen (HLA) and single nucleotide polymorphism genotypes were imputed from the GWAS data, with direct HLA typing performed on selected cases to validate HLA predictions. Four replication cases that were unavailable for the GWAS were genotyped by direct HLA typing, yielding an overall total of 10 flupirtine DILI cases. RESULTS: In the six flupirtine DILI cases included in the GWAS, we found a significant enrichment of the DRB1*16:01-DQB1*05:02 haplotype compared with the controls (minor allele frequency cases 0.25 and minor allele frequency controls 0.013; P=1.4 × 10(-5)). We estimated an odds ratio for haplotype carriers of 18.7 (95% confidence interval 2.5-140.5, P=0.002) using population-specific HLA control data. The result was replicated in four additional cases, also with a haplotype frequency of 0.25. In the combined cohort (six GWAS plus four replication cases), the haplotype was also significant (odds ratio 18.7, 95% confidence interval 4.31-81.42, P=6.7 × 10(-5)). CONCLUSION: We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally.
OBJECTIVE: Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown. MATERIALS AND METHODS: Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10,588 population controls. DILI was diagnosed by causality assessment and expert review. Human leucocyte antigen (HLA) and single nucleotide polymorphism genotypes were imputed from the GWAS data, with direct HLA typing performed on selected cases to validate HLA predictions. Four replication cases that were unavailable for the GWAS were genotyped by direct HLA typing, yielding an overall total of 10 flupirtine DILI cases. RESULTS: In the six flupirtine DILI cases included in the GWAS, we found a significant enrichment of the DRB1*16:01-DQB1*05:02 haplotype compared with the controls (minor allele frequency cases 0.25 and minor allele frequency controls 0.013; P=1.4 × 10(-5)). We estimated an odds ratio for haplotype carriers of 18.7 (95% confidence interval 2.5-140.5, P=0.002) using population-specific HLA control data. The result was replicated in four additional cases, also with a haplotype frequency of 0.25. In the combined cohort (six GWAS plus four replication cases), the haplotype was also significant (odds ratio 18.7, 95% confidence interval 4.31-81.42, P=6.7 × 10(-5)). CONCLUSION: We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally.
Authors: Konrad W Wurm; Frieda-Marie Bartz; Lukas Schulig; Anja Bodtke; Patrick J Bednarski; Andreas Link Journal: ChemMedChem Date: 2022-07-07 Impact factor: 3.540
Authors: Paola Nicoletti; Guruprasad P Aithal; Einar S Bjornsson; Raul J Andrade; Ashley Sawle; Marco Arrese; Huiman X Barnhart; Emmanuelle Bondon-Guitton; Paul H Hayashi; Fernando Bessone; Alfonso Carvajal; Ingolf Cascorbi; Elizabeth T Cirulli; Naga Chalasani; Anita Conforti; Sally A Coulthard; Mark J Daly; Christopher P Day; John F Dillon; Robert J Fontana; Jane I Grove; Pär Hallberg; Nelia Hernández; Luisa Ibáñez; Gerd A Kullak-Ublick; Tarja Laitinen; Dominique Larrey; M Isabel Lucena; Anke H Maitland-van der Zee; Jennifer H Martin; Mariam Molokhia; Munir Pirmohamed; Elizabeth E Powell; Shengying Qin; Jose Serrano; Camilla Stephens; Andrew Stolz; Mia Wadelius; Paul B Watkins; Aris Floratos; Yufeng Shen; Matthew R Nelson; Thomas J Urban; Ann K Daly Journal: Gastroenterology Date: 2016-12-30 Impact factor: 22.682