Genomweite Assoziationsstudien in der Hepatologie

Zusammenfassung

Genomweite Assoziationsstudien gewinnen zunehmend an Bedeutung und wurden kürzlich auch erstmals bei hepatobiliären Erkrankungen durchgeführt. Die meisten Leberkrankungen sind multikausale (komplexe) Krankheiten, die durch vielfältige Interaktionen zwischen multiplen genetischen und exogenen Faktoren moduliert werden. Ziel der genomweiten Assoziationsstudien ist die Identifizierung der genetischen Risikofaktoren, die zur Entstehung oder Progression einer Erkrankung beitragen. Hierzu werden in großen Patientenkohorten genetische Marker, die das gesamte Genom abdecken, mit klinischen Phänotypen korreliert. So konnten „Risikogene” für Gallensteine, die Fettlebererkrankung, primäre cholestatische Lebererkrankungen und die chronische Hepatitis-C-Virus (HCV)-Infektion sowie die Fibroseprogression bei HCV-infizierten Patienten ermittelt werden. Für diese Patientengruppe wurden erstmals „Gensignaturen” erstellt, mit denen die Interaktion mehrerer Polymorphismen quantitativ erfasst und mit der Fibroseprogression korreliert werden konnten. Neue Erkenntnisse über bisher unbekannte genetische Determinanten von Lebererkrankungen können Mausmodelle geben, wobei in großen experimentellen Kreuzungen suszeptibler und resistenter Inzuchtmausstämme Phänotypen charakterisiert und genomweit mit genetischen Markern assoziiert werden. Die Resultate der genomweiten Studien bei Maus und Mensch tragen dazu bei, die Pathogenese komplexer Lebererkrankungen besser zu verstehen und zukünftig „personalisierte” Strategien für ihre Prävention und Therapie zu entwickeln.

Abstract

Genomewide association studies (GWAS) are being reported for an increasing number of common diseases, including first reports on GWAS for hepatobiliary diseases. Most common liver diseases are multifactorial (complex) diseases that are modified by higher-order interactions between multiple genetic and environmental risk factors. The aim of GWAS is to identify the genetic risk factors contributing to disease susceptibility and/or progression. In GWAS, large patient cohorts are genotyped for genetic markers that cover the whole genome, and genotypes are associated with phenotypes by contingency tests and regression analyses. Recent GWAS have identified ”risk genes” for gallstones, fatty liver, primary cholestatic liver diseases and chronic hepatitis C virus (HCV) infection as well as fibrosis progression in HCV-infected patients. For the latter patients, ”gene signatures” were developed that are composed of multiple risk variants and are associated with progressive liver fibrosis. Furthermore, mouse models are an important tool to identify novel genetic determinants of complex liver diseases. In large experimental crosses of susceptible and resistant inbred mouse strains, phenotypes are correlated with genome-wide markers by genetic linkage analyses. The findings from genome-wide studies in mice and men may contribute to a better understanding of the pathogenesis of complex liver diseases and provide a framework for the development of ”personalised” strategies for prediction, early prevention and therapy.

Schlüsselwörter

Genvarianten - Gallensteine - Leberfibrose - Polymorphismen - Virushepatitis

Key words

gene variants - gallstones - liver fibrosis - polymorphisms - viral hepatitis

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