title: Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.
abstract: Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 β-galactosamide α-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.
authors.affiliation: 1 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
authors.forename: Zelalem
authors.initials: Z
authors.lastname: Petros
authors.affiliation: 1 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.affiliation: 2 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital , Huddinge C1:68, Karolinska Institutet, Stockholm, Sweden .
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000009:adverse effects; D015815:Cell Adhesion Molecules; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D004008:Diclofenac / Q000009:adverse effects / Q000031:analogs & derivatives; D005436:Floxacillin / Q000009:adverse effects; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D000077341:Lapatinib; D008099:Liver / Q000293:injuries / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D011799:Quinazolines / Q000009:adverse effects
chemical_list: D015815:Cell Adhesion Molecules; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D011506:Proteins; D011799:Quinazolines; C104952:RIPOR2 protein, human; D000077341:Lapatinib; D004008:Diclofenac; D005436:Floxacillin; D019980:Amoxicillin-Potassium Clavulanate Combination; C473384:lumiracoxib
keywords: GWAS; disruptive innovation; drug discovery and development; drug-induced hepatotoxicity; drug-induced liver injury; genome-wide study; translational research