Z Gastroenterol 2020; 58(01): e25
DOI: 10.1055/s-0039-3402166
Poster Visit Session III Metabolism (incl. NAFLD): Friday, February 14, 2020, 4:40 pm – 5:25 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

PNPLA3 and HSD17B13 gene variants exert opposite effects on fatty liver phenotypes: results from the FLAG cohort

M Krawczyk
1   Department of Medicine II, Saarland University Medical Center, Homburg, Germany
,
JM Schattenberg
2   Mainz University Hospital, Mainz, Germany
,
L Schubert
3   Gastroenterologie am Bayerischen Platz, Berlin, Germany
,
N Dikopoulos
4   Gastroenterologische Schwerpunktpraxis, Dornstadt, Germany
,
J Schwenzer
5   Bauchzentrum Biesdorf, Berlin, Germany
,
M Muche
6   Charité Campus Benjamin Franklin, Berlin, Germany
,
J Wiegand
7   Division of Gastroenterology, University Hospital Leipzig, Leipzig, Germany
,
G Felten
8   Gastroenterologische Praxis Herne, Herne, Germany
,
R Heyne
9   Leberzentrum am Checkpoint, Berlin, Germany
,
P Ingiliz
10   Zentrum für Infektiologie Prenzlauer Berg, Berlin, Germany
,
A Schmidt
11   Magen-Darm-Zentrum Wiener Platz, Köln, Germany
,
K Stein
12   Praxis für Infektiologie und Hepatologie Magdeburg, Magdeburg, Germany
,
M Manns
13   Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
,
S Zeuzem
14   Department of Gastroenterology, Hepatology, Endocrinology and Nutrition, University Hospital, Goethe University, Frankfurt am Main, Germany
,
P Buggisch
15   IFI Institut für interdisziplinäre Medizin, Hamburg, Germany
,
F Lammert
1   Department of Medicine II, Saarland University Medical Center, Homburg, Germany
,
WP Hofmann
3   Gastroenterologie am Bayerischen Platz, Berlin, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

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Background:

Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition common in overweight and obese individuals. The PNPLA3 p.I148 M variant represents a major genetic determinant of NAFLD progression. Recently the loss-of-function HSD17B13 polymorphism rs72613567 was reported to be hepatoprotective in patients with chronic liver diseases (Abdul-Husn et al. NEJM 2018). Here we investigate the effects of the PNPLA3 and HSD17B13 variant on NAFLD phenotypes in a "real life" cohort of German NAFLD patients.

Patients and methods:

All patients were recruited within the Fatty Liver Assessment in Germany (FLAG) program, a multicenter cohort study covering private and public outpatient clinics. The PNPLA3 p.I148 M and the HSD17B13 rs72613567 polymorphisms were genotyped using allelic discrimination assays. The control cohort comprises 174 healthy individuals. The effects of both variants were analysed in contingency tables and regression analyses.

Results:

Overall, the study cohort comprised 475 individuals (255 men) with NAFLD. The PNPLA3, but not the HSD17B13, polymorphism deviated significantly (P < 0.001) from Hardy-Weinberg equilibrium (HWE) in the entire FLAG cohort due to overrepresentation of the prosteatotic risk allele. The PNPLA3 p.I148 M variant was more prevalent among FLAG patients as compared to healthy controls and increased the risk of developing NAFLD (common OR = 2.47, P = 5 × 10 – 09). It also correlated with serum AST (P = 0.04) and ALT (P = 0.01) activities. Notably, among carriers of the PNPLA3 p. 148 M allele, presence of the HSD17B13 allele was associated with lower AST (P = 0.006) and ALT (P = 0.002) activities, underscoring the protective effects of this variant. Finally, the PNPLA3 p.I148 M polymorphism was associated with an increased risk of presenting with liver stiffness ≥9.2 kPa (common OR = 1.50, P = 0.03), i.e. with significant fibrosis (Caballería et al. Clin Gastroenterol Hepatol 2018) and this association remained significant (P = 0.04) in a multivariate model including the HSD17B13 polymorphism.

Discussion:

Previous genetic studies in NAFLD patients were mostly performed in tertiary academic referral centres. Here, by analysing patients from a "real life" NAFLD cohort, we further underscore the role of the PNPLA3 variant as the central genetic trigger and modulator of NAFLD. We also demonstrate that the HSD17B13 polymorphism can attenuate some of the harmful PNPLA3-associated effects.