Z Gastroenterol 2020; 58(01): e9
DOI: 10.1055/s-0039-3402121
Poster Visit Session I Basic Hepatology (Fibrogenesis, NPC, Transport): Friday, February 14, 2020, 12:30 pm – 1:15 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Common genetic variant c.711A>T in the hepatobiliary phospholipid translocator ABCB4 as risk factor for liver fibrosis

W Smyk
1   Saarland University Medical Center, Saarland University, Department of Medicine II, Homburg, Germany
2   Medical University of Warsaw, Liver and Internal Medicine Unit, Warsaw, Poland
,
R Hall
1   Saarland University Medical Center, Saarland University, Department of Medicine II, Homburg, Germany
,
S Weber
1   Saarland University Medical Center, Saarland University, Department of Medicine II, Homburg, Germany
,
F Grünhage
1   Saarland University Medical Center, Saarland University, Department of Medicine II, Homburg, Germany
,
F Lammert
1   Saarland University Medical Center, Saarland University, Department of Medicine II, Homburg, Germany
,
M Krawczyk
1   Saarland University Medical Center, Saarland University, Department of Medicine II, Homburg, Germany
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Publikationsverlauf

Publikationsdatum:
03. Januar 2020 (online)

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    Question:

    Chronic liver diseases (CLD) result in liver fibrosis. Recently it was demonstrated (Serra-Burriel et al. J Hepatol 2019) that a transient elastography (TE) threshold of 9.1 kPa has the best accuracy for the prediction of relevant liver fibrosis (i.e., stages ≥ F2). Previously we showed that the common PNPLA3 (adiponutrin) p.I148 M polymorphism is associated with liver cirrhosis and that carriers of the procholestatic ABCB4 c.711T allele, who are also positive for the PNPLA3 variant, might be at risk of progressive liver injury. Here, we investigate the association between this ABCB4 polymorphism and liver stiffness as well as the influence of ABCB4 and PNPLA3 on fibrosis in a mouse model of chronic cholestasis.

    Methods:

    Prospectively we recruited 712 patients (278 women, age 50 ± 13 years, BMI 24.4 ± 4.3 kg/m2) with CLD. Liver stiffness was measured non-invasively using TE. The ABCB4 c.711A>T polymorphism was genotyped by a PCR-based assay. Pnpla3 expression as well as liver injury were analysed in the Abcb4-/- mice and controls animals.

    Results:

    Median liver stiffness was 6.7 kPa and 226 individuals (31.7%) presented with TE ≥9.1 kPa. The minor allele frequency of the ABCB4 c.711 was 0.18 in the human cohort. The ABCB4 variant was significantly (P = 0.02, OR = 1.33) associated with liver stiffness ≥9.1 kPa. In a multivariate model including non-genetic profibrogenic factors, the ABCB4 variant (P = 0.05, OR = 1.43) as well as BMI (P = 0.04, OR = 1.04) and age (P < 0.01, OR = 1.02) all proved to be independent risk factors for fibrosis stage ≥ F2. Moreover, Abcb4 deficient mice showed enhanced liver injury (reflected by increased Col1a2 expression and elevated collagen contents), which was coupled with significantly (P < 0.05) lower expression of Pnpla3 as compared to wild-type mice.

    Conclusions:

    The procholestatic ABCB4 c.711T allele might represent a common genetic risk factor for clinically relevant liver fibrosis. Lower expression of adiponutrin in fibrotic livers of the Abcb4-/- mice alludes to the interaction between phospholipid content and PNPLA3 expression in progressive liver injury. Our results suggest that the Abcb4-/- might serve as the animal model to further investigate the role of PNPLA3 in liver fibrosis.


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