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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.
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
URL: http://dx.doi.org/10.1016/j.jhep.2014.02.030
DOI: 10.1016/j.jhep.2014.02.030
PubMed id: 24607626
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