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Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.
J Hepatol 2014; 61(1):75-81JH

Abstract

BACKGROUND & AIMS

Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD.

METHODS

PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD.

RESULTS

Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001).

CONCLUSIONS

Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.

Authors+Show Affiliations

Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK.Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK. Electronic address: helen.reeves@ncl.ac.uk.Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24607626

Citation

Liu, Y-L, et al. "Carriage of the PNPLA3 Rs738409 C >G Polymorphism Confers an Increased Risk of Non-alcoholic Fatty Liver Disease Associated Hepatocellular Carcinoma." Journal of Hepatology, vol. 61, no. 1, 2014, pp. 75-81.
Liu YL, Patman GL, Leathart JB, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61(1):75-81.
Liu, Y. L., Patman, G. L., Leathart, J. B., Piguet, A. C., Burt, A. D., Dufour, J. F., ... Anstee, Q. M. (2014). Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. Journal of Hepatology, 61(1), pp. 75-81. doi:10.1016/j.jhep.2014.02.030.
Liu YL, et al. Carriage of the PNPLA3 Rs738409 C >G Polymorphism Confers an Increased Risk of Non-alcoholic Fatty Liver Disease Associated Hepatocellular Carcinoma. J Hepatol. 2014;61(1):75-81. PubMed PMID: 24607626.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. AU - Liu,Y-L, AU - Patman,G L, AU - Leathart,J B S, AU - Piguet,A-C, AU - Burt,A D, AU - Dufour,J-F, AU - Day,C P, AU - Daly,A K, AU - Reeves,H L, AU - Anstee,Q M, Y1 - 2014/03/06/ PY - 2013/11/11/received PY - 2014/02/26/revised PY - 2014/02/27/accepted PY - 2014/3/11/entrez PY - 2014/3/13/pubmed PY - 2015/5/12/medline KW - Gene KW - HCC KW - Hepatocellular carcinoma KW - NAFLD KW - NASH KW - PNPLA3 KW - Steatohepatitis SP - 75 EP - 81 JF - Journal of hepatology JO - J. Hepatol. VL - 61 IS - 1 N2 - BACKGROUND & AIMS: Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS: PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS: Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS: Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/24607626/Carriage_of_the_PNPLA3_rs738409_C_>G_polymorphism_confers_an_increased_risk_of_non_alcoholic_fatty_liver_disease_associated_hepatocellular_carcinoma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(14)00138-X DB - PRIME DP - Unbound Medicine ER -