Genome-Wide Association Studies in Drug-Induced Liver Injury: Step Change in Understanding the Pathogenesis

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

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ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Seminars in Liver Disease ◽

10.1055/s-0038-1667299 ◽

2018 ◽

Vol 38 (04) ◽

pp. 299-307 ◽

Cited By ~ 21

Author(s):

Matthias Reichert ◽

Frank Lammert

Keyword(s):

Intrahepatic Cholestasis ◽

Association Studies ◽

Compound Heterozygous ◽

Genome Wide Association Studies ◽

Therapeutic Approaches ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Genome Wide ◽

Abcb4 Gene ◽

Type 3

AbstractATP-binding cassette subfamily B member 4 (ABCB4) is a phospholipid translocator at the canalicular membrane of the hepatocyte, which “flops” phosphatidylcholine into bile. Dysfunction of this transporter due to ABCB4 gene variants can cause liver diseases and has been called ABCB4 deficiency. Several diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3), low phospholipid-associated cholelithiasis (LPAC), a subgroup of patients developing intrahepatic cholestasis of pregnancy (ICP), drug-induced liver injury and chronic cholangiopathy with biliary fibrosis and cirrhosis were attributed to ABCB4 deficiency and characterized in the past decade. LPAC and ICP are usually caused by monoallelic variants, whereas patients affected by PFIC3 are homozygous or compound heterozygous carriers of ABCB4 variants. Treatment with ursodeoxycholic acid is often effective, but as the more severe forms of ABCB4 deficiency progress, nevertheless, new diagnostic and therapeutic approaches are warranted. Current functional classifications for ABCB4 deficiency–associated mutations can guide the development of novel genotype–based targeted pharmacotherapies for these conditions. Recently, increasing evidence from genome-wide association studies is emerging on associations of ABCB4 variants with hepatobiliary malignancies.

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

OMICS A Journal of Integrative Biology ◽

10.1089/omi.2017.0006 ◽

2017 ◽

Vol 21 (3) ◽

pp. 123-131 ◽

Cited By ~ 5

Author(s):

Zelalem Petros ◽

Eyasu Makonnen ◽

Eleni Aklillu

Keyword(s):

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Next Generation ◽

Drug Induced ◽

Genome Wide ◽

Looking Back

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Genetics in Common Liver Diseases: From Pathophysiology to Precise Treatment

Digestive Diseases ◽

10.1159/000444554 ◽

2016 ◽

Vol 34 (4) ◽

pp. 391-395 ◽

Cited By ~ 3

Author(s):

Frank Lammert

Keyword(s):

Liver Disease ◽

Liver Diseases ◽

Association Studies ◽

Clinical Care ◽

Genome Wide Association Studies ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

The Past ◽

Genomic Technologies ◽

Genome Wide

In the past 2 decades, advances in genetics have improved our understanding of liver disease and physiology. Firstly, developments in genomic technologies drove the identification of genes responsible for monogenic (Mendelian) liver diseases. Over the last decade, genome-wide association studies allowed for the dissection of the genetic susceptibility to complex liver diseases such as fatty liver disease and drug-induced liver injury, in which environmental co-factors play critical roles. The findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and risk factors and have already pointed to new disease treatments. This is illustrated by the interaction of alcohol, overnutrition and the PNPLA3 gene, which represents an ‘infernal triangle' for the liver. In the future, genetics will allow further stratification of liver diseases and contribute to personalized (precision) medicine, offering novel opportunities for translational research and clinical care of our patients.

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