The ABCB4 p.T175A allele might be associated with increased liver injury: analysis of two independent cohorts of patients with chronic liver diseases and NAFLD

M Krawczyk; M Rau; J Schattenberg; F Grünhage; H Bantel; A Pathil; M Demir; J Kluwe; T Boettler; A Geier; F Lammert

doi:10.1055/s-0036-1586970

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

The ABCB4 p.T175A allele might be associated with increased liver injury: analysis of two independent cohorts of patients with chronic liver diseases and NAFLD

M Krawczyk ¹, M Rau ², J Schattenberg ³, F Grünhage ¹, H Bantel ⁴, A Pathil ⁵, M Demir ⁶, J Kluwe ⁷, T Boettler ⁸, A Geier ², F Lammert ¹

¹Saarland University Hospital, Department of Medicine II, Homburg, Deutschland
²Division of Hepatology, Department of Medicine II, University Hospital, Würzburg, Deutschland
³I. Department of Medicine, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Deutschland
⁴Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Deutschland
⁵Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Deutschland
⁶Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Deutschland
⁷I. Department of Medicine, Hamburg University Medical Center, Hamburg, Deutschland
⁸Department of Medicine II, University Hospital, Freiburg, Deutschland

Abstract

Introduction: Hepatic fibrosis represents the uniform response to chronic liver injury. Lately large-scale whole-genome sequencing identified the common variant c.711A>T of the hepatobiliary lecithin transporter ABCB4 as risk factor for hepatobiliary diseases and cirrhosis (Gudbjartsson et al. Nat Genet 2015). Thus we now assess this variant along with the less frequent procholestatic ABCB4 p.T175A mutation (Delaunay et al. Hepatology 2015) for their involvement in liver injury in two large cohorts of patients.

Patients and methods: The first cohort comprised 678 patients (age 50.2 ± 12.7 years, 414 men) with chronic liver diseases and liver fibrosis quantified using transient elastography (Fibroscan) (Krawczyk et al. J Hepatol 2011). Liver biopsy results were available in 150 patients. The second cohort was composed of 516 patients with NAFLD (48.2 ± 13.4 years, 239 men) recruited in the framework of the German NAFLD CSG group. In this cohort liver biopsy was performed in 309 individuals. The ABCB4 variants c.711A>T and p.A175T were genotyped using Taqman assays.

Results: In a total of 1,194 genotyped patients, 30 carried the p.T175A variant. The c.711A>T procholestatic polymorphism was present in 798 individuals. In the first cohort, carriers of the p.A175T variant presented with significantly increased TE levels (P = 0.02) as compared to patients with the common genotype. Among five biopsied carriers of the risk allele, three presented with fibrosis stage F4. In the NAFLD group, seven of the nine carriers of the minor p.A175T allele (78%) had been scheduled for liver biopsy. This variant was however not associated with histological fibrosis stages or liver function tests (all P > 0.05). Presence of the ABCB4 c.711 variant was in turn not associated with liver stiffness, results of liver biopsy, or liver function tests (all P > 0.05).

Conclusions: Carriers of the ABCB4 p.A175T risk allele who suffer from chronic liver disease might be at increased risk of progressive liver injury and fibrosis. This effect appears to be less pronounced in NAFLD patients. Our observation points to a sensitizing role of procholestatic mutations and underscores the value of elastography for integrated assessment of pathogenic pathways in chronic liver disease.