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The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis
Author(s) -
Reuken Philipp A.,
Lutz Philipp,
Casper Markus,
AlHerwi Eihab,
Stengel Sven,
Spengler Ulrich,
Stallmach Andreas,
Lammert Frank,
Nischalke Hans Dieter,
Bruns Tony
Publication year - 2019
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14239
Subject(s) - atg16l1 , medicine , gastroenterology , cohort , cirrhosis , hepatocellular carcinoma , odds ratio , allele , oncology , biology , gene , genetics , disease , crohn's disease
Background and 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 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. Results 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. 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.