Molekulargenetik der Cholesterin-Cholelithiasis: Identifizierung humaner und muriner Gallensteingene

Zusammenfassung

Die Cholesterin-Cholelithiasis, eine der verbreitetsten gastroenterologischen Erkrankungen in westlichen Ländern, ist eine polygene Erkrankung, die aus einer gestörten biliären Cholesterinhomöostase resultiert. Durch Assoziationsstudien zwischen Gallensteinphänotypen und einzelnen Genen konnten bisher sechs humane Gallensteinkandidatengene identifiziert werden. Polymorphismen in den Genen der Apolipoproteine B und E, der Phospholipid-Flippase (ABCB4), des Cholesterinester-Transferproteins (CETP), der Cholesterin-7α-Hydroxylase (CYP7A1) und des ilealen Gallensäurentransporters (SLC10A2) korrelieren mit dem Auftreten von Gallensteinen. Die Quantitative Trait-Locus-(QTL-)Analyse erlaubt die Lokalisation weiterer unbekannter Gallensteingene in Inzuchtmäusen. Durch die unterschiedliche Gallensteinprädisposition verschiedener Inzuchtstämme konnten 5 lithogene (Lith-)Loci identifiziert werden. Als attraktive Kandidatengene wurden hepatobiliäre Lipidtransportproteine wie die Gallensäurenexportpumpe (Abcb11) und Schlüsselenzyme des Lipoproteinstoffwechsels wie die hepatische Lipase (Lipc) etabliert. Der rasche Fortschritt der Genomprojekte bildet die Grundlage zur Analyse der orthologen LITH-Gene bei Gallensteinpatienten, die neue Ansätze für eine patientenbezogene Risikoabschätzung und pharmakologische Präventionsstrategien eröffnen könnte.

Abstract

Cholesterol cholelithiasis is one of the most common gastroenterological diseases in Western countries. It is a polygenic disease resulting from disturbed biliary cholesterol homeostasis. Association studies identified six human gallstone candidate genes. Polymorphisms in the genes encoding the apolipoproteins B and E, phospholipid flippase (ABCB4), cholesterol ester transfer protein (CETP), cholesterol-7α-hydroxylase (CYP7A1) and ileal bile acid transporter (SLC10A2) are correlated with gallstone prevalence. Quantitative Trait Locus (QTL) analysis localises additional unknown gallstone genes in inbred mice. Based on the natural variation of cholesterol gallstone susceptibility among different inbred strains, 5 lithogenic (Lith) loci have been identified. Hepatobiliary transporters (e. g. bile salt export pump Abcb11) and key proteins of the lipoprotein metabolism (e. g. hepatic lipase Lipc) could be established as creedal candidate genes for Lith loci. The rapid progress of mouse and human genome projects provides the basis for the analysis of orthologous human LITH genes in gallstone patients, which might offer new prospects for individual risk assessment and molecular targets for stone prevention.

Schlüsselwörter

Cholesteringallensteine - Polygene Erkrankung - Assoziationsstudien - Kandidatengene - Quantitative Trait-Locus-Analyse - Inzuchtmäuse - Murine Gallensteinkarte - Lith-Locus - Gallensteinprävention

Keywords

Cholesterol Gallstones - Polygenic Disease - Asscociation Studies - Candidate Genes - Quantitative Trait Locus Analysis - Inbred Mice - Murine Gallstone Map - Lith Locus - Primary Prevention

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4 Ein QTL erhält einen Namen, wenn der LOD-Score > 3,3-4,3 ist, was einem p < 0,0001 entspricht. Der LOD-Score ist der Logarithmus des Verhältnisses der Wahrscheinlichkeit, die experimentellen Daten bei genetischer Kopplung zu beobachten, und der Wahrscheinlichkeit, die Daten zufällig zu beobachten.

4