Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.

Zelalem Petros, Eyasu Makonnen, Eleni Aklillu
Author Information
  1. Zelalem Petros: 1 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
  2. Eyasu Makonnen: 1 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
  3. Eleni Aklillu: 2 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital , Huddinge C1:68, Karolinska Institutet, Stockholm, Sweden .

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.

Keywords

References

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MeSH Term

Amoxicillin-Potassium Clavulanate Combination
Cell Adhesion Molecules
Chemical and Drug Induced Liver Injury
Diclofenac
Floxacillin
Genome-Wide Association Study
Genotype
HLA-B Antigens
HLA-DQ beta-Chains
HLA-DRB1 Chains
Humans
Lapatinib
Liver
Proteins
Quinazolines

Chemicals

Cell Adhesion Molecules
HLA-B Antigens
HLA-B57 antigen
HLA-DQ beta-Chains
HLA-DQB1 antigen
HLA-DRB1 Chains
Proteins
Quinazolines
RIPOR2 protein, human
Lapatinib
Diclofenac
Floxacillin
Amoxicillin-Potassium Clavulanate Combination
lumiracoxib

Word Cloud

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