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Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

Lookup NU author(s): Misti McCainORCiD, Dr Luca Miele, Professor Helen ReevesORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019, The Author(s). Nonalcoholic fatty liver disease (NAFLD) is a rising cause of hepatocellular carcinoma (HCC). We examined whether inherited pathogenic variants in candidate genes (n = 181) were enriched in patients with NAFLD-HCC. To this end, we resequenced peripheral blood DNA of 142 NAFLD-HCC, 59 NAFLD with advanced fibrosis, and 50 controls, and considered 404 healthy individuals from 1000 G. Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. In NAFLD-HCC patients, we detected an enrichment in pathogenic (p = 0.024), and likely pathogenic variants (p = 1.9*10 −6 ), particularly in APOB (p = 0.047). APOB variants were associated with lower circulating triglycerides and higher HDL cholesterol (p < 0.01). A genetic risk score predicted NAFLD-HCC (OR 4.96, 3.29–7.55; p = 5.1*10 −16 ), outperforming the diagnostic accuracy of common genetic risk variants, and of clinical risk factors (p < 0.05). In conclusion, rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development.

Publication metadata

Author(s): Pelusi S, Baselli G, Pietrelli A, Dongiovanni P, Donati B, McCain MV, Meroni M, Fracanzani AL, Romagnoli R, Petta S, Grieco A, Miele L, Soardo G, Bugianesi E, Fargion S, Aghemo A, D'Ambrosio R, Xing C, Romeo S, De Francesco R, Reeves HL, Valenti LVC

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2019

Volume: 9

Issue: 1

Online publication date: 06/03/2019

Acceptance date: 23/01/2019

Date deposited: 20/03/2019

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group


DOI: 10.1038/s41598-019-39998-2

PubMed id: 30842500


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