Toggle Main Menu Toggle Search

Open Access padlockePrints

Carriage of the PNPLA3 rs738409 C>G Polymorphism Confers an Increased Risk of Non-Alcoholic Fatty Liver Disease Associated Hepatocellular Carcinoma

Lookup NU author(s): Dr Yang-Lin Liu, Dr Gillian Patman, Julian Leathart, Professor Alastair BurtORCiD, Professor Chris Day, Professor Ann DalyORCiD, Professor Helen ReevesORCiD, Professor Quentin AnsteeORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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.

Publication metadata

Author(s): Liu Y-L, Patman GL, Leathart J, Piguet A-C, Burt AD, Dufour J-F, Day CP, Daly AK, Reeves HL, Anstee QM

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2014

Volume: 61

Issue: 1

Pages: 75-81

Print publication date: 01/07/2014

Online publication date: 06/03/2014

Acceptance date: 27/02/2014

Date deposited: 29/08/2014

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier BV


DOI: 10.1016/j.jhep.2014.02.030

PubMed id: 24607626


Altmetrics provided by Altmetric


Funder referenceFunder name
Clinical Senior Lectureship Award from the Higher Education Funding Council for England (HEFCE)
Newcastle NIHR Biomedical Research Centre
FP7/2007-2013'Fatty Liver Inhibition of Progression' (FLIP) - European Union Seventh Framework Programme
Health-F2-2009-241762'Fatty Liver Inhibition of Progression' (FLIP) - European Union Seventh Framework Programme