title: Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.
abstract: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.
  
  
  
  We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs.
  
  
  
  We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224.
  
  
  
  In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoletti
authors.affiliation: National Institute for Health Research, Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospital, National Health Service Trust, and University of Nottingham, Nottingham, United Kingdom.
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authors.affiliation: Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
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authors.lastname: Bjornsson
authors.affiliation: Unidad de Gestión Clínica Digestivo, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Málaga, Spain.
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authors.affiliation: Department of Systems Biology, Columbia University, New York, New York.
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authors.affiliation: Departmento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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authors.affiliation: Department of Internal Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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authors.affiliation: Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina.
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authors.affiliation: Liver Unit, Centre Hospitalier Universitaire, St Eloi Hospital, Montpellier, France.
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authors.affiliation: Unidad de Gestión Clínica Digestivo, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Málaga, Spain.
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authors.affiliation: Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
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authors.affiliation: Unidad de Gestión Clínica Digestivo, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Málaga, Spain.
authors.forename: Camilla
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mesh_terms: D000483:Alleles; D000928:Antidepressive Agents / Q000009:adverse effects; D000935:Antifungal Agents / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D011345:Fenofibrate / Q000009:adverse effects; D005805:Genes, MHC Class I / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D000960:Hypolipidemic Agents / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000009:adverse effects; D016017:Odds Ratio; D010641:Phenotype; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D020280:Sertraline / Q000009:adverse effects; D000077291:Terbinafine; D013988:Ticlopidine / Q000009:adverse effects; D044465:White People / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D000935:Antifungal Agents; D015234:HLA-A Antigens; C082945:HLA-A*33 antigen; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D000077291:Terbinafine; D013988:Ticlopidine; D020280:Sertraline; D011345:Fenofibrate
keywords: Anti-Fungal Agent; Liver Damage; Medication; Side Effect