Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background and aims</jats:title><jats:p>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 <jats:italic>ATG16L1</jats:italic> is associated with an increased risk for hepatocellular carcinoma (HCC) in cirrhosis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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. <jats:italic>ATG16L1</jats:italic> p.T300A (rs2241880) and <jats:italic>PNPLA3</jats:italic> p.I148M (rs738409) variants were determined by real‐time PCR.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The G allele of the <jats:italic>ATG16L1</jats:italic> p.T300A variant was more frequent in patients with HCC compared to controls without HCC in the derivation cohort (0.62 vs. 0.51, <jats:italic>P</jats:italic> = .022) and in the validation cohort (0.59 vs. 0.50, <jats:italic>P</jats:italic> = .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 <jats:italic>PNPLA3</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The common germ‐line <jats:italic>ATG16L1</jats:italic> gene variant is a risk factor for HCC in patients with cirrhosis. Personalized strategies employing the genetic risk conferred by <jats:italic>ATG16L1</jats:italic> and <jats:italic>PNPLA3</jats:italic> may be used for risk‐based surveillance in cirrhosis.</jats:p></jats:sec>