Z Gastroenterol 2019; 57(01): e68
DOI: 10.1055/s-0038-1677228
4. Tumors
Georg Thieme Verlag KG Stuttgart · New York

The ATG16L1 Gene Variant rs2241880 (p.T300A) Is Associated With Susceptibility to HCC In Patients with Cirrhosis

P Reuken
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
,
P Lutz
2   Department of Internal Medicine I, University of Bonn, Bonn, Germany
3   German Center for Infection Research, Bonn, Germany
,
M Casper
4   Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
,
E Al-Herwi
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
,
S Stengel
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
,
U Spengler
2   Department of Internal Medicine I, University of Bonn, Bonn, Germany
3   German Center for Infection Research, Bonn, Germany
,
A Stallmach
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
,
F Lammert
4   Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
,
HD Nischalke
2   Department of Internal Medicine I, University of Bonn, Bonn, Germany
3   German Center for Infection Research, Bonn, Germany
,
T Bruns
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

Also available at
 

Background & Aims:

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.

Methods:

A case control study was performed at three university hospitals 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.I148 M (rs738409) variants were determined by real-time PCR.

Results:

The G allele of ATG16L1 causing the 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 = 0.022) and in the validation cohort (0.59 vs. 0.50, P = 0.045). 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. Patients carrying three or more of the investigated risk alleles had a significant higher risk of HCC compared to wild type alleles in both risk genes. 1-year-survival after diagnosis of HCC was the lowest in patients with AA genotype (25.0%± 15.3%) as compared to patients with AG (40.0%± 7.7%) or GG (40.8%± 10.0%) genotypes (P = 0.31 in log-rank test for trend).

Conclusion:

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.