Genetics in Common Liver Diseases: From Pathophysiology to Precise Treatment

2016 ◽  
Vol 34 (4) ◽  
pp. 391-395 ◽  
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.

Liver and Statins: A Critical Appraisal of the Evidence

2019 ◽  
Vol 25 (42) ◽  
pp. 5835-5846 ◽  
Author(s):  
Anna Licata ◽  
Antonina Giammanco ◽  
Maria Giovanna Minissale ◽  
Salvatore Pagano ◽  
Salvatore Petta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Association Studies ◽  
Organic Anion ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Organic Anion Transporting Polypeptide ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Underlying Mechanisms

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.

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

2018 ◽  
Vol 38 (04) ◽  
pp. 299-307 ◽  
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.

Genome-Wide Association Studies of Drug-Induced Liver Injury Make Progress Beyond the HLA Region

2019 ◽  
Vol 157 (4) ◽  
pp. 1167-1168
Author(s):  
Galen E.B. Wright ◽  
Britt I. Drögemöller ◽  
Colin J.D. Ross ◽  
Bruce C. Carleton
Keyword(s):  
Liver Injury ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Genome Wide

scholarly journals Genetic epidemiology and Mendelian randomization for informing disease therapeutics: conceptual and methodological challenges

2017 ◽  
Author(s):  
Lavinia Paternoster ◽  
Kate Tilling ◽  
George Davey Smith
Keyword(s):  
Genetic Epidemiology ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Disease Treatment ◽  
The Past ◽  
Genome Wide ◽  
Perceived Benefit ◽  
Progression Of Disease ◽  
High Yields

The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets (1-4), but this has yet to be realised at a level reflecting expectation. One reason for this, we suggest, is that GWAS to date have generally not focused on phenotypes that directly relate to the progression of disease, and thus speak to disease treatment.

Genetic Methodologies and Applications

2017 ◽  
Author(s):  
Shaun M. Purcell
Keyword(s):  
Mental Illness ◽  
Genetic Risk ◽  
Genetic Basis ◽  
Common Mental Disorders ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
The Past ◽  
Genome Wide ◽  
Experimental Approaches ◽  
Large Families

Mental illness is highly heritable, yet it has been difficult historically to identify the specific genes that comprise that risk. This difficulty resides in the fact that the genetic risk for all common mental disorders is polygenic, with perhaps hundreds of genetic variations, each of small effect, contributing to the overall risk. Despite these challenges, the field has made dramatic advances over the past decade in beginning to understand the genetic basis of mental illness. This chapter provides an overview of the experimental approaches used, beginning with epidemiology and population genetics to define the heritability of an illness, to classic studies of large families and linkage disequilibrium analysis, to genome-wide investigations including genome-wide association studies (GWAS), exome sequencing, and whole genome sequencing. Increasingly, these genetic advances are being understood within the biological context of disease pathophysiology.

scholarly journals Perspective: The Clinical Use of Polygenic Risk Scores: Race, Ethnicity, and Health Disparities

2019 ◽  
Vol 29 (3) ◽  
pp. 513-516 ◽  
Author(s):  
Megan C. Roberts ◽  
Muin J. Khoury ◽  
George A. Mensah
Keyword(s):  
Precision Medicine ◽  
Association Studies ◽  
Clinical Care ◽  
Genomic Research ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Adverse Health Outcomes ◽  
Genome Wide ◽  
Disease Risks

Polygenic risk scores (PRS) are an emerging precision medicine tool based on multiple gene variants that, taken alone, have weak associations with disease risks, but collec­tively may enhance disease predictive value in the population. However, the benefit of PRS may not be equal among non-European populations, as they are under-represented in genome-wide association studies (GWAS) that serve as the basis for PRS develop­ment. In this perspective, we discuss a path forward, which includes: 1) inclusion of underrepresented populations in PRS research; 2) global efforts to build capacity for genomic research; 3) equitable imple­mentation of these tools in clinical practice; and 4) traditional public health approaches to reduce risk of adverse health outcomes as an important component to precision health. As precision medicine is imple­mented in clinical care, researchers must ensure that advances from PRS research will benefit all.Ethn Dis.2019;29(3):513-516; doi:10.18865/ed.29.3.513.

Genomics Overview

2010 ◽  
Author(s):  
W Gregory Feero
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Disease Risk ◽  
Association Studies ◽  
Clinical Care ◽  
Family Health ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Sequencing Technologies ◽  
Genome Wide

New genomic applications are affecting internal medicine subspecialties and will soon affect the practices of all physicians. This chapter discusses the fields of genetics versus genomics and details the fundamentals of a genomic approach to health care. It includes special considerations such as the intersection between genomics and evidence-based medicine, genetic discrimination, the regulation of genetic testing, and the marketing of genetic testing directly to consumers. The chapter looks at genome-wide association studies and clinical care, as well as sequencing technologies. Tables offer examples of patterns of inheritance, clinical recommendations and red flags raised by family history, and intended uses for genetic tests. One figure shows an example pedigree obtained by using the US surgeon general's My Family Health Portrait family history tool, while the other shows the chromosomal locations of genetic markers associated with disease risk discovered in genome-wide association studies between 2005 and 2009. This chapter contains 41 references.

Genomics Overview

2010 ◽  
Author(s):  
W Gregory Feero
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Disease Risk ◽  
Association Studies ◽  
Clinical Care ◽  
Family Health ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Sequencing Technologies ◽  
Genome Wide

New genomic applications are affecting internal medicine subspecialties and will soon affect the practices of all physicians. This chapter discusses the fields of genetics versus genomics and details the fundamentals of a genomic approach to health care. It includes special considerations such as the intersection between genomics and evidence-based medicine, genetic discrimination, the regulation of genetic testing, and the marketing of genetic testing directly to consumers. The chapter looks at genome-wide association studies and clinical care, as well as sequencing technologies. Tables offer examples of patterns of inheritance, clinical recommendations and red flags raised by family history, and intended uses for genetic tests. One figure shows an example pedigree obtained by using the US surgeon general's My Family Health Portrait family history tool, while the other shows the chromosomal locations of genetic markers associated with disease risk discovered in genome-wide association studies between 2005 and 2009. This chapter contains 41 references.

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