Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases

  • Khlaiphuengsin, Apichaya (Department of Biochemistry Research Unit of Hepatitis and Liver Cancer, Chulalongkorn University) ;
  • Kiatbumrung, Rattanaporn (Department of Biochemistry Research Unit of Hepatitis and Liver Cancer, Chulalongkorn University) ;
  • Payungporn, Sunchai (Department of Biochemistry Research Unit of Hepatitis and Liver Cancer, Chulalongkorn University) ;
  • Pinjaroen, Nutcha (Department of Radiology, Faculty of Medicine, Chulalongkorn University) ;
  • Tangkijvanich, Pisit (Department of Biochemistry Research Unit of Hepatitis and Liver Cancer, Chulalongkorn University)
  • Published : 2016.01.11


Background: The aim of this study was to evaluate any association between a single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409, C>G) and the development and prognosis in patients with hepatocellular carcinoma (HCC). Materials and Methods: Two hundred heathy controls and 388 HCC cases were included: 211 with HBV, 98 patients with HCV, 29 with alcoholic steatohepatitis (ASH) and 52 with non-alcoholic steatohepatitis (NASH). The SNP was determined by real-time PCR based on TaqMan assays. Results: The prevalence of rs738409 genotypes CC, CG and GG in controls was 91 (45.5%), 88 (44.0%), and 21 (10.5%), respectively, while the corresponding genotypes in all patients with HCC was 158 (40.7%), 178 (45.9%), and 52 (13.4%). The GG genotype had significantly higher distribution in patients with ASH/NASH-related HCC compared with controls (OR=2.34, 95% CI=1.16-4.71, P=0.018), and viral-related HCC cases (OR=2.15, 95% CI=1.13-4.08, P=0.020). However, the frequency of the GG genotype was similar between controls and patients with viral-related HCC. At initial diagnosis, HBV-related HCC were larger and at more advanced BCLC stage than the other HCC groups. There were no significant differences between the GG and non-GG groups regarding clinical characteristics, tumor stage and overall survival. Conclusions: These data suggest an influence of the PNPLA3 polymorphism on the occurrence of HCC in patients with ASH/NASH but not among those with chronic viral hepatitis. However, the polymorphism was not associated with the prognosis of HCC.


Supported by : Chulalongkorn University


  1. Brouwer WP, van der Meer AJ, Boonstra A, et al (2015). The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis B patients. Liver Int, 35, 438-47.
  2. Bruix J, Sherman M (2011). Management of hepatocellular carcinoma: an update. Hepatology, 53, 1020-2.
  3. Day CP (2006). From fat to inflammation. Gastroenterology, 130, 207-10.
  4. Falleti E, Fabris C, Cmet S, et al (2011). PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int, 31, 1137-43.
  5. Friedrich K, Wannhoff A, Kattner S, et al (2014). PNPLA3 in end-stage liver disease: alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival. J Gastroenterol Hepatol, 29, 1477-84.
  6. Gao J, Xie L, Yang WS, et al (2012). Risk factors of hepatocellular carcinoma--current status and perspectives. Asian Pac J Cancer Prev, 13, 743-52.
  7. Guyot E, Sutton A, Rufat P, et al (2013). PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis. J Hepatol, 58, 312-8.
  8. He S, McPhaul C, Li JZ, et al (2010). A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem, 285, 6706-15.
  9. Huang Y, He S, Li JZ, et al (2010). A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A, 107, 7892-7.
  10. Jenkins CM, Mancuso DJ, Yan W, et al (2004). Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem, 279, 48968-75.
  11. Jin F, Xiong WJ, Jing JC, et al (2011). Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review. J Cancer Res Clin Oncol, 137, 1095-104.
  12. Liu YL, Patman GL, Leathart JB, et al (2014). Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol, 61, 75-81.
  13. Llovet JM, Di Bisceglie AM, Bruix J, et al (2008). Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst, 100, 698-711.
  14. Nault JC (2014). Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract Res Clin Gastroenterol, 28, 937-47.
  15. Nischalke HD, Berger C, Luda C, et al (2011). The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis. PLoS One, 6, 27087.
  16. Patton HM, Patel K, Behling C, et al (2004). The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol, 40, 484-90.
  17. Pingitore P, Pirazzi C, Mancina RM, et al (2014). Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochim Biophys Acta, 1841, 574-80.
  18. Romeo S, Kozlitina J, Xing C, et al (2008). Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet, 40, 1461-5.
  19. Rubbia-Brandt L, Quadri R, Abid K, et al (2000). Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol, 33, 106-15.
  20. Salameh H, Raff E, Erwin A, et al (2015). PNPLA3 Gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. The American journal of gastroenterology, 110, 846-56.
  21. Sato M, Kato N, Tateishi R, et al (2014). Impact of PNPLA3 polymorphisms on the development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Hepatol Res, 44, 137-44.
  22. Singal AG, Manjunath H, Yopp AC, et al (2014). The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. The American journal of gastroenterology, 109, 325-34.
  23. Smagris E, BasuRay S, Li J, et al (2015). Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology, 61, 108-18.
  24. Sookoian S, Castano GO, Burgueno AL, et al (2009). A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res, 50, 2111-6.
  25. Sopipong W, Tangkijvanich P, Payungporn S, et al (2013). The KIF1B (rs17401966) single nucleotide polymorphism is not associated with the development of HBV-related hepatocellular carcinoma in Thai patients. Asian Pac J Cancer Prev, 14, 2865-9.
  26. Stickel F, Buch S, Lau K, et al (2011). Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology, 53, 86-95.
  27. Takeuchi Y, Ikeda F, Moritou Y, et al (2013). The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis. J Gastroenterol, 48, 405-12.
  28. Tangkijvanich P, Hirsch P, Theamboonlers A, et al (1999). Association of hepatitis viruses with hepatocellular carcinoma in Thailand. J Gastroenterol, 34, 227-33.
  29. Trepo E, Guyot E, Ganne-Carrie N, et al (2012). PNPLA3 (rs738409 C>G) is a common risk variant associated with hepatocellular carcinoma in alcoholic cirrhosis. Hepatology, 55, 1307-8.
  30. Trepo E, Nahon P, Bontempi G, et al (2014). Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology, 59, 2170-7.
  31. Trepo E, Pradat P, Potthoff A, et al (2011). Impact of patatinlike phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology, 54, 60-9.
  32. Valenti L, Motta BM, Soardo G, et al (2013). PNPLA3 I148M polymorphism, clinical presentation, and survival in patients with hepatocellular carcinoma. PLoS One, 8, 75982.
  33. Vigano M, Valenti L, Lampertico P, et al (2013). Patatin-like phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis B. Hepatology, 58, 1245-52.
  34. Yuan X, Waterworth D, Perry JR, et al (2008). Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet, 83, 520-8.
  35. Zampino R, Coppola N, Cirillo G, et al (2015). Patatin-Like Phospholipase Domain-Containing 3 I148M variant is associated with liver steatosis and fat distribution in Chronic Hepatitis B. Dig Dis Sci.

Cited by

  1. Association between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma risk: an updated meta-analysis vol.38, pp.9, 2016,
  2. An ErChen and YinChen Decoction Ameliorates High-Fat-Induced Nonalcoholic Steatohepatitis in Rats by Regulating JNK1 Signaling Pathway vol.2017, pp.1741-4288, 2017,
  3. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases pp.00207136, 2018,