The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus.
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.
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.|Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Misuzu
M
Ueyama
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Nao
N
Nishida
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.
Masaaki
M
Korenaga
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Keiko
K
Korenaga
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.|Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Erina
E
Kumagai
Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan.
Hidekatsu
H
Yanai
Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan.
Hiroki
H
Adachi
Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan.
Hisayuki
H
Katsuyama
Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan.
Sumie
S
Moriyama
Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan.
Hidetaka
H
Hamasaki
Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan.
Akahito
A
Sako
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Masaya
M
Sugiyama
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Yoshihiko
Y
Aoki
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Masatoshi
M
Imamura
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Kazumoto
K
Murata
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Naohiko
N
Masaki
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Takumi
T
Kawaguchi
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Takuji
T
Torimura
Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
Hideyuki
H
Hyogo
Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
Hiroshi
H
Aikata
Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.
Kiyoaki
K
Ito
Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan.|Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
Yoshio
Y
Sumida
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Akio
A
Kanazawa
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Hirotaka
H
Watada
Department of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
Koji
K
Okamoto
Department of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
Kenjiro
K
Honda
Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Kazuyoshi
K
Kon
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Tatsuya
T
Kanto
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
Masashi
M
Mizokami
Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Sumio
S
Watanabe
D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006505:Hepatitis / Q000150:complications; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D008049:Lipase; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C430460:JAZF1 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
Hepatocellular carcinoma; JAZF1; PNPLA3; Type 2 diabetes mellitus