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The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis.

Authors
  • Reuken, Philipp A1
  • Lutz, Philipp2, 3
  • Casper, Markus4
  • Al-Herwi, Eihab1
  • Stengel, Sven1
  • Spengler, Ulrich2, 3
  • Stallmach, Andreas1
  • Lammert, Frank4
  • Nischalke, Hans Dieter2, 3
  • Bruns, Tony1, 5
  • 1 Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Jena, Germany. , (Germany)
  • 2 Department of Internal Medicine I, University of Bonn, Bonn, Germany. , (Germany)
  • 3 German Center for Infection Research, Bonn, Germany. , (Germany)
  • 4 Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany. , (Germany)
  • 5 Medical Department III, University Hospital of Aachen, Aachen, Germany. , (Germany)
Type
Published Article
Journal
Liver international : official journal of the International Association for the Study of the Liver
Publication Date
Dec 01, 2019
Volume
39
Issue
12
Pages
2360–2367
Identifiers
DOI: 10.1111/liv.14239
PMID: 31484215
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Protein and organelle turnover by autophagy is a key component to maintain cellular homeostasis. Loss of the autophagy protein ATG16L1 is associated with reduced bacterial killing and aberrant interleukin-1β production, perpetuating inflammation and carcinogenesis. Here we hypothesized that the functional p.T300A gene variant in ATG16L1 is associated with an increased risk for hepatocellular carcinoma (HCC) in cirrhosis. A case-control study was performed using a prospective derivation cohort (107 patients with HCC and 101 controls) and an independent validation cohort (124 patients with HCC and 108 controls) of patients with cirrhosis of any aetiology. ATG16L1 p.T300A (rs2241880) and PNPLA3 p.I148M (rs738409) variants were determined by real-time PCR. The G allele of the ATG16L1 p.T300A variant was more frequent in patients with HCC compared to controls without HCC in the derivation cohort (0.62 vs. 0.51, P = .022) and in the validation cohort (0.59 vs. 0.50, P = .045). In combined analysis, the odds ratios (OR) were 1.76 (95% CI: 1.07-2.88) for G allele positivity and 2.43 (95% CI: 1.37-4.31) for p.T300A G allele homozygosity. This association was independent from the presence of a PNPLA3 variant, which was also associated with HCC (OR 2.10; 95% CI: 1.20-3.66), and it remained significant after adjustment for male sex, age and aetiology in multivariate analysis. The common germ-line ATG16L1 gene variant is a risk factor for HCC in patients with cirrhosis. Personalized strategies employing the genetic risk conferred by ATG16L1 and PNPLA3 may be used for risk-based surveillance in cirrhosis. © 2019 The Authors. Liver International published by John Wiley & Sons Ltd.

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