Genetic variants in adult liver diseases

Abstract

In the last decades, understanding of genetic variants contributing to liver disease development has considerably improved through novel genotyping techniques. Genetic variants of single genes are known to be decisive for the development of monogenetic liver diseases of varying severity. Identification of genetic variants is an important part of the diagnostic process, e. g. the majority of patients with high iron [Fe] (HFE)-associated hemochromatosis carry the homozygous mutation p.C282Y. Detection of mutations in genes encoding hepatobiliary transport proteins like familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance protein 3 (MDR3) is the basis to differentiate various forms of intrahepatic cholestasis. Moreover, genetic variants in a variety of genes are known to act as disease modifiers and represent risk factors for disease progression and the development of cirrhosis or even hepatocellular carcinoma. Success of drug treatment or appearance of severe side effects can also be influenced by specific genetic variants. All these aspects underscore the increasing importance of genetic variants, which in the future may help to identify patients at risk for disease progression or help to guide treatment decisions. In the present overview, specific frequent genetic variants are summarized that play roles in monogenetic liver diseases, forms of intrahepatic cholestasis, gallstone development, fatty liver disease, drug-induced liver injury, and liver disease progression as well as hepatocellular carcinoma development.

Zusammenfassung

In den letzten Jahrzehnten hat sich das Verständnis von Lebererkrankungen mit Hilfe neuer Techniken erheblich verbessert. Genetische Varianten einzelner Gene sind für die Entwicklung monogenetischer Lebererkrankungen unterschiedlichen Schweregrads entscheidend. Die Identifizierung genetischer Varianten ist ein wichtiger Teil des Diagnostikprozesses, z. B. trägt die Mehrheit der Patienten mit high iron [Fe] (HFE)-assoziierter Hämochromatose die homozygote Mutation p.C282Y. Der Nachweis von Mutationen in Genen, die hepatobiliäre Transportproteine wie FIC1 (familial intrahepatic cholestasis 1), BSEP (bile salt export pump) oder MDR3 (multidrug resistance protein 3) kodieren, ist die Grundlage für die Diagnose verschiedener Formen intrahepatischer Cholestasen. Des Weiteren beeinflussen genetische Varianten in einer Vielzahl von Genen den Krankheitsverlauf unterschiedlicher Lebererkrankungen und stellen Risikofaktoren für die Entwicklung einer Leberzirrhose oder des hepatozellulären Karzinoms dar. Der Behandlungserfolg oder das Auftreten schwerer Nebenwirkungen kann ebenfalls durch spezifische genetische Varianten beeinflusst werden. All diese Aspekte verdeutlichen, dass die Einbeziehung genetischer Informationen im Bereich Diagnostik, Risikostratifizierung und Therapieentscheidung bei Patienten mit Lebererkrankungen in Zukunft weiter an Bedeutung gewinnen wird. In der vorliegenden Arbeit sind spezifische genetische Varianten zusammengefasst, die bei monogenetischen Lebererkrankungen, intrahepatischen Cholestasen, Gallensteinentwicklung, Fettleber, medikamentös-toxischer Leberschädigung, Leberzirrhose und hepatozellulärem Karzinom eine Rolle spielen.

Schlüsselwörter

monogenetisch - Polymorphismus - autosomal - Genotyp - Phänotyp - Krankheitsmodifikator

Key Words

monogenetic - single nucleotide polymorphism - autosomal - genotype - phenotype - disease modifier

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