title: HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury.
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.
  
  
  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)).
  
  
  CONCLUSIONS
  We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally.
authors.affiliation: 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.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoletti
authors.forename: Anneke N
authors.initials: AN
authors.lastname: Werk
authors.forename: Ashley
authors.initials: A
authors.lastname: Sawle
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Sally A
authors.initials: SA
authors.lastname: Coulthard
authors.forename: Einar S
authors.initials: ES
authors.lastname: Bjornsson
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Aris
authors.initials: A
authors.lastname: Floratos
authors.forename: Thomas
authors.initials: T
authors.lastname: Stammschulte
authors.forename: Ursula
authors.initials: U
authors.lastname: Gundert-Remy
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.forename: Guruprasad P
authors.initials: GP
authors.lastname: Aithal
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D000631:Aminopyridines; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C034161:flupirtine