Misuzu Ueyama1,2, Nao Nishida1, Masaaki Korenaga3, Keiko Korenaga1, Erina Kumagai1,2, Hidekatsu Yanai4, Hiroki Adachi4, Hisayuki Katsuyama4, Sumie Moriyama4, Hidetaka Hamasaki4, Akahito Sako4, Masaya Sugiyama1, Yoshihiko Aoki1, Masatoshi Imamura1, Kazumoto Murata1, Naohiko Masaki1, Takumi Kawaguchi5, Takuji Torimura5, Hideyuki Hyogo6, Hiroshi Aikata6, Kiyoaki Ito7, Yoshio Sumida8,9, Akio Kanazawa10, Hirotaka Watada10, Koji Okamoto11, Kenjiro Honda11, Kazuyoshi Kon2, Tatsuya Kanto1, Masashi Mizokami1, Sumio Watanabe2. 1. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan. 2. Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan. 3. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan. dmkorenaga@hospk.ncgm.go.jp. 4. Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan. 5. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. 6. Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan. 7. Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan. 8. Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan. 9. Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan. 10. Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan. 11. Department of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
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.
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 JAZF1rs864745 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.
Entities:
Keywords:
Hepatocellular carcinoma; JAZF1; PNPLA3; Type 2 diabetes mellitus
Authors: Iona Cheng; Christian P Caberto; Annette Lum-Jones; Ann Seifried; Lynne R Wilkens; Fredrick R Schumacher; Kristine R Monroe; Unhee Lim; Maarit Tiirikainen; Laurence N Kolonel; Brian E Henderson; Daniel O Stram; Christopher A Haiman; Loïc Le Marchand Journal: Gut Date: 2011-05-20 Impact factor: 23.059
Authors: Gilles Thomas; Kevin B Jacobs; Meredith Yeager; Peter Kraft; Sholom Wacholder; Nick Orr; Kai Yu; Nilanjan Chatterjee; Robert Welch; Amy Hutchinson; Andrew Crenshaw; Geraldine Cancel-Tassin; Brian J Staats; Zhaoming Wang; Jesus Gonzalez-Bosquet; Jun Fang; Xiang Deng; Sonja I Berndt; Eugenia E Calle; Heather Spencer Feigelson; Michael J Thun; Carmen Rodriguez; Demetrius Albanes; Jarmo Virtamo; Stephanie Weinstein; Fredrick R Schumacher; Edward Giovannucci; Walter C Willett; Olivier Cussenot; Antoine Valeri; Gerald L Andriole; E David Crawford; Margaret Tucker; Daniela S Gerhard; Joseph F Fraumeni; Robert Hoover; Richard B Hayes; David J Hunter; Stephen J Chanock Journal: Nat Genet Date: 2008-02-10 Impact factor: 38.330