DOI QR코드

DOI QR Code

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

Abstract

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.

Keywords

PNPLA3;HBV;HCV;ASH;NASH;HCC development;prognosis

Acknowledgement

Supported by : Chulalongkorn University

References

  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. https://doi.org/10.1111/liv.12695
  2. Bruix J, Sherman M (2011). Management of hepatocellular carcinoma: an update. Hepatology, 53, 1020-2. https://doi.org/10.1002/hep.24199
  3. Day CP (2006). From fat to inflammation. Gastroenterology, 130, 207-10. https://doi.org/10.1053/j.gastro.2005.11.017
  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. https://doi.org/10.1111/j.1478-3231.2011.02534.x
  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. https://doi.org/10.1111/jgh.12540
  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. https://doi.org/10.7314/APJCP.2012.13.3.743
  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. https://doi.org/10.1016/j.jhep.2012.09.036
  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. https://doi.org/10.1074/jbc.M109.064501
  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. https://doi.org/10.1073/pnas.1003585107
  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. https://doi.org/10.1074/jbc.M407841200
  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. https://doi.org/10.1007/s00432-010-0970-0
  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. https://doi.org/10.1016/j.jhep.2014.02.030
  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. https://doi.org/10.1093/jnci/djn134
  14. Nault JC (2014). Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract Res Clin Gastroenterol, 28, 937-47. https://doi.org/10.1016/j.bpg.2014.08.006
  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. https://doi.org/10.1371/journal.pone.0027087
  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. https://doi.org/10.1016/j.bbalip.2013.12.006
  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. https://doi.org/10.1038/ng.257
  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. https://doi.org/10.1016/S0168-8278(00)80166-X
  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. https://doi.org/10.1038/ajg.2015.137
  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. https://doi.org/10.1111/hepr.12258
  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. https://doi.org/10.1038/ajg.2013.476
  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. https://doi.org/10.1002/hep.27242
  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. https://doi.org/10.1194/jlr.P900013-JLR200
  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. https://doi.org/10.7314/APJCP.2013.14.5.2865
  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. https://doi.org/10.1002/hep.24017
  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. https://doi.org/10.1007/s00535-012-0647-3
  28. Tangkijvanich P, Hirsch P, Theamboonlers A, et al (1999). Association of hepatitis viruses with hepatocellular carcinoma in Thailand. J Gastroenterol, 34, 227-33. https://doi.org/10.1007/s005350050248
  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. https://doi.org/10.1002/hep.25518
  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. https://doi.org/10.1002/hep.26767
  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. https://doi.org/10.1002/hep.24350
  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. https://doi.org/10.1371/journal.pone.0075982
  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. https://doi.org/10.1002/hep.26445
  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. https://doi.org/10.1016/j.ajhg.2008.09.012
  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, https://doi.org/10.1007/s13258-016-0428-0
  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, https://doi.org/10.1155/2017/4603701
  3. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases pp.00207136, 2018, https://doi.org/10.1002/ijc.31910