The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus

J Gastroenterol. 2016 Apr;51(4):370-9. doi: 10.1007/s00535-015-1116-6. Epub 2015 Sep 3.


Background: Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). T2DM is associated with non-alcoholic steatohepatitis (NASH), which is a major cause of non-HBV and non-HCV-related HCC; nevertheless, it has been difficult to identify those patients with T2DM who have a high risk of developing HCC. The aim of this study was to identify genetic determinants that predispose T2DM patients to HCC by genotyping T2DM susceptibility loci and PNPLA3.

Methods: We recruited 389 patients with T2DM who satisfied the following three criteria: negative for HBs-Ag and anti-HCV Ab, alcohol intake <60 g/day, and history of T2DM >10 years. These patients were divided into two groups: T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). We genotyped 51 single-nucleotide polymorphisms (SNPs) previously reported as T2DM or NASH susceptibility loci (PNPLA3) compared between the DM-HCC and DM-non-HCC groups with regard to allele frequencies at each SNP.

Results: The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 2.53, p = 1.05 × 10(-5)). Among individuals homozygous for the PNPLA3 G allele (n = 115), the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 3.44, p = 0.0002).

Conclusions: PNPLA3 and JAZF1 were associated with non-HBV and non-HCV-related HCC development among Japanese patients with T2DM.

Keywords: Hepatocellular carcinoma; JAZF1; PNPLA3; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Hepatitis / complications
  • Humans
  • Lipase / genetics*
  • Liver Neoplasms / etiology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors


  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • JAZF1 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • Lipase
  • adiponutrin, human