PMID- 28253087
OWN - NLM
STAT- MEDLINE
DCOM- 20171013
LR  - 20201214
IS  - 1557-8100 (Electronic)
IS  - 1536-2310 (Print)
IS  - 1536-2310 (Linking)
VI  - 21
IP  - 3
DP  - 2017 Mar
TI  - Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: 
      Looking Back-Looking Forward to Next-Generation Innovation.
PG  - 123-131
LID - 10.1089/omi.2017.0006 [doi]
AB  - 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 beta-galactosamide alpha-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.
FAU - Petros, Zelalem
AU  - Petros Z
AD  - 1 Department of Pharmacology, School of Medicine, College of Health Sciences, 
      Addis Ababa University , Addis Ababa, Ethiopia .
FAU - Makonnen, Eyasu
AU  - Makonnen E
AD  - 1 Department of Pharmacology, School of Medicine, College of Health Sciences, 
      Addis Ababa University , Addis Ababa, Ethiopia .
FAU - Aklillu, Eleni
AU  - Aklillu E
AD  - 2 Division of Clinical Pharmacology, Department of Laboratory Medicine, 
      Karolinska University Hospital , Huddinge C1:68, Karolinska Institutet, 
      Stockholm, Sweden .
LA  - eng
PT  - Journal Article
DEP - 20170216
PL  - United States
TA  - OMICS
JT  - Omics : a journal of integrative biology
JID - 101131135
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B57 antigen)
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DQB1 antigen)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (Proteins)
RN  - 0 (Quinazolines)
RN  - 0 (RIPOR2 protein, human)
RN  - 0VUA21238F (Lapatinib)
RN  - 144O8QL0L1 (Diclofenac)
RN  - 43B2M34G2V (Floxacillin)
RN  - 74469-00-4 (Amoxicillin-Potassium Clavulanate Combination)
RN  - V91T9204HU (lumiracoxib)
SB  - IM
MH  - Amoxicillin-Potassium Clavulanate Combination/adverse effects
MH  - Cell Adhesion Molecules
MH  - Chemical and Drug Induced Liver Injury/*genetics
MH  - Diclofenac/adverse effects/analogs & derivatives
MH  - Floxacillin/adverse effects
MH  - Genome-Wide Association Study/*methods
MH  - Genotype
MH  - HLA-B Antigens/genetics
MH  - HLA-DQ beta-Chains/genetics
MH  - HLA-DRB1 Chains/genetics
MH  - Humans
MH  - Lapatinib
MH  - Liver/injuries/metabolism
MH  - Proteins/genetics
MH  - Quinazolines/adverse effects
PMC - PMC5346905
OTO - NOTNLM
OT  - GWAS
OT  - disruptive innovation
OT  - drug discovery and development
OT  - drug-induced hepatotoxicity
OT  - drug-induced liver injury
OT  - genome-wide study
OT  - translational research
COIS- The authors declare that no conflicting financial interests exist.
EDAT- 2017/03/03 06:00
MHDA- 2017/10/14 06:00
PMCR- 2018/03/01
CRDT- 2017/03/03 06:00
PHST- 2017/03/03 06:00 [entrez]
PHST- 2017/03/03 06:00 [pubmed]
PHST- 2017/10/14 06:00 [medline]
PHST- 2018/03/01 00:00 [pmc-release]
AID - 10.1089/omi.2017.0006 [pii]
AID - 10.1089/omi.2017.0006 [doi]
PST - ppublish
SO  - OMICS. 2017 Mar;21(3):123-131. doi: 10.1089/omi.2017.0006. Epub 2017 Feb 16.