Abstract
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.
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Abbreviations
- T2DM:
-
Type 2 diabetes mellitus
- NASH:
-
Non-alcoholic steatohepatitis
- HCC:
-
Hepatocellular carcinoma
- SNPs:
-
Single-nucleotide polymorphisms
- HBV:
-
Hepatitis B virus
- HCV:
-
Hepatitis C virus
- HBs-Ag:
-
Hepatitis B surface antigen
- anti-HCV Ab:
-
Anti-hepatitis C virus antibody
- PNPLA3:
-
Patatin-like phospholipase domain-containing protein 3
- JAZF1:
-
Juxtaposed with another zinc finger protein 1
- anti-HBc Ab:
-
Anti-hepatitis B core antibody
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Acknowledgments
We thank Ms. Yoriko Mawatari, Ms. Mayumi Ishii, Ms. Takayo Tsuchiura, Ms. Kozue Sugimoto, and Ms. Noriko Ota for their technical support. This study was supported by grants (25-202, 26-206) from the National Center for Global Health and Medicine in Japan and the Ministry of Education, Culture, Sports, Science, and Technology (No. 25461019) and by a research award from the Liver Forum in Kyoto; it was also supported in part by the Ministry of Health, Labour, and Welfare of Japan.
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M. Ueyama and N. Nishida contributed equally to this work.
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Ueyama, M., Nishida, N., Korenaga, M. et al. The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus. J Gastroenterol 51, 370–379 (2016). https://doi.org/10.1007/s00535-015-1116-6
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DOI: https://doi.org/10.1007/s00535-015-1116-6