PNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis.
BACKGROUND
PNPLA3 rs738409 polymorphism is associated with fatty liver disease, alcoholic or non-alcoholic (NAFLD) and hepatocellular carcinoma (HCC). TM6SF2 rs58542926 is clearly associated with NAFLD, but it is not clearly associated with HCC. The relationship between TM6SF2 rs58542926 and HCC and the potential synergistic effect of TM6SF2 and PNPLA3 variants in modifying the risk of HCC are not known.


OBJECTIVE
This study assessed the interaction between PNPLA3 rs738409 and TM6SF2 rs58542926 variants in the conditioning of HCC development.


METHODS
A total of 511 cirrhotic patients (44% alcohol-related, 56% viral, 57.5% liver transplanted) were retrospectively investigated for HCC occurrence. PNPLA3 rs734809 and TM6SF2 rs58542926 were genotyped using restriction fragment length polymorphism and real-time allelic discrimination polymerase chain reaction methods.


RESULTS
Patients with HCC were more likely to be PNPLA3 rs734809 G/G homozygotes (41/150 vs. 60/361, p=0.009) or TM6SF2 rs58542926 C/T-T/T (27/150 vs. 41/361, p=0.044). The presence of either PNPLA3 G/G or TM6SF2*/T identified high-risk genotypes for HCC, which were strongly associated with HCC (64/150 vs. 93/361, p=0.0002). This association was evident in alcohol-related (p=0.0007) but not in viral cirrhosis.


CONCLUSIONS
TM6SF2 C/T or T/T in conjunction with PNPLA3 G/G variants may be potential genetic risk factors for developing HCC in alcohol-related cirrhosis.
Department of Medicine and Pathology Clinical and Experimental, Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Italy.
Edmondo
E
Falleti
Department of Medicine and Pathology Clinical and Experimental, Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Italy.
Annarosa
A
Cussigh
Department of Medicine and Pathology Clinical and Experimental, Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Italy.
Sara
S
Cmet
Department of Medicine and Pathology Clinical and Experimental, Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Italy.
Carlo
C
Fabris
Department of Medicine and Pathology Clinical and Experimental, Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Italy. Electronic address: pierluigi.toniutto@uniud.it.
Pierluigi
P
Toniutto
D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D012189:Retrospective Studies; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D008049:Lipase; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
Genetic polymorphisms; Hepatocellular carcinoma; Lipids; Steatosis