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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

An Editorial to this article was published on 31 October 2015

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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Author notes

  1. Masaaki Korenaga

    Present address: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan

Authors and Affiliations

  1. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan

    Misuzu Ueyama, Nao Nishida, Keiko Korenaga, Erina Kumagai, Masaya Sugiyama, Yoshihiko Aoki, Masatoshi Imamura, Kazumoto Murata, Naohiko Masaki, Tatsuya Kanto & Masashi Mizokami

  2. Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan

    Misuzu Ueyama, Erina Kumagai, Kazuyoshi Kon & Sumio Watanabe

  3. Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan

    Hidekatsu Yanai, Hiroki Adachi, Hisayuki Katsuyama, Sumie Moriyama, Hidetaka Hamasaki & Akahito Sako

  4. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

    Takumi Kawaguchi & Takuji Torimura

  5. Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan

    Hideyuki Hyogo & Hiroshi Aikata

  6. Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

    Kiyoaki Ito

  7. Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan

    Yoshio Sumida

  8. Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan

    Yoshio Sumida

  9. Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan

    Akio Kanazawa & Hirotaka Watada

  10. Department of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan

    Koji Okamoto & Kenjiro Honda

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  1. Misuzu Ueyama
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Correspondence to Masaaki Korenaga.

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The authors declare that they have no conflict of interest.

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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

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