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Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clin...

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Autores principales: Bianco, Cristiana, Jamialahmadi, Oveis, Pelusi, Serena, Baselli, Guido, Dongiovanni, Paola, Zanoni, Irene, Santoro, Luigi, Maier, Silvia, Liguori, Antonio, Meroni, Marica, Borroni, Vittorio, D’Ambrosio, Roberta, Spagnuolo, Rocco, Alisi, Anna, Federico, Alessandro, Bugianesi, Elisabetta, Petta, Salvatore, Miele, Luca, Vespasiani-Gentilucci, Umberto, Anstee, Quentin M., Stickel, Felix, Hampe, Jochen, Fischer, Janett, Berg, Thomas, Fracanzani, Anna Ludovica, Soardo, Giorgio, Reeves, Helen, Prati, Daniele, Romeo, Stefano, Valenti, Luca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987554/
https://www.ncbi.nlm.nih.gov/pubmed/33248170
http://dx.doi.org/10.1016/j.jhep.2020.11.024
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author Bianco, Cristiana
Jamialahmadi, Oveis
Pelusi, Serena
Baselli, Guido
Dongiovanni, Paola
Zanoni, Irene
Santoro, Luigi
Maier, Silvia
Liguori, Antonio
Meroni, Marica
Borroni, Vittorio
D’Ambrosio, Roberta
Spagnuolo, Rocco
Alisi, Anna
Federico, Alessandro
Bugianesi, Elisabetta
Petta, Salvatore
Miele, Luca
Vespasiani-Gentilucci, Umberto
Anstee, Quentin M.
Stickel, Felix
Hampe, Jochen
Fischer, Janett
Berg, Thomas
Fracanzani, Anna Ludovica
Soardo, Giorgio
Reeves, Helen
Prati, Daniele
Romeo, Stefano
Valenti, Luca
author_facet Bianco, Cristiana
Jamialahmadi, Oveis
Pelusi, Serena
Baselli, Guido
Dongiovanni, Paola
Zanoni, Irene
Santoro, Luigi
Maier, Silvia
Liguori, Antonio
Meroni, Marica
Borroni, Vittorio
D’Ambrosio, Roberta
Spagnuolo, Rocco
Alisi, Anna
Federico, Alessandro
Bugianesi, Elisabetta
Petta, Salvatore
Miele, Luca
Vespasiani-Gentilucci, Umberto
Anstee, Quentin M.
Stickel, Felix
Hampe, Jochen
Fischer, Janett
Berg, Thomas
Fracanzani, Anna Ludovica
Soardo, Giorgio
Reeves, Helen
Prati, Daniele
Romeo, Stefano
Valenti, Luca
author_sort Bianco, Cristiana
collection PubMed
description BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. METHODS: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). RESULTS: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10(-13)). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10(-7)). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10(-5)) and without cirrhosis (p <0.05). CONCLUSIONS: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. LAY SUMMARY: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.
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spelling pubmed-79875542021-04-01 Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores Bianco, Cristiana Jamialahmadi, Oveis Pelusi, Serena Baselli, Guido Dongiovanni, Paola Zanoni, Irene Santoro, Luigi Maier, Silvia Liguori, Antonio Meroni, Marica Borroni, Vittorio D’Ambrosio, Roberta Spagnuolo, Rocco Alisi, Anna Federico, Alessandro Bugianesi, Elisabetta Petta, Salvatore Miele, Luca Vespasiani-Gentilucci, Umberto Anstee, Quentin M. Stickel, Felix Hampe, Jochen Fischer, Janett Berg, Thomas Fracanzani, Anna Ludovica Soardo, Giorgio Reeves, Helen Prati, Daniele Romeo, Stefano Valenti, Luca J Hepatol Research Article BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. METHODS: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). RESULTS: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10(-13)). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10(-7)). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10(-5)) and without cirrhosis (p <0.05). CONCLUSIONS: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. LAY SUMMARY: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population. Elsevier 2021-04 /pmc/articles/PMC7987554/ /pubmed/33248170 http://dx.doi.org/10.1016/j.jhep.2020.11.024 Text en © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Bianco, Cristiana
Jamialahmadi, Oveis
Pelusi, Serena
Baselli, Guido
Dongiovanni, Paola
Zanoni, Irene
Santoro, Luigi
Maier, Silvia
Liguori, Antonio
Meroni, Marica
Borroni, Vittorio
D’Ambrosio, Roberta
Spagnuolo, Rocco
Alisi, Anna
Federico, Alessandro
Bugianesi, Elisabetta
Petta, Salvatore
Miele, Luca
Vespasiani-Gentilucci, Umberto
Anstee, Quentin M.
Stickel, Felix
Hampe, Jochen
Fischer, Janett
Berg, Thomas
Fracanzani, Anna Ludovica
Soardo, Giorgio
Reeves, Helen
Prati, Daniele
Romeo, Stefano
Valenti, Luca
Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
title Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
title_full Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
title_fullStr Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
title_full_unstemmed Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
title_short Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
title_sort non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987554/
https://www.ncbi.nlm.nih.gov/pubmed/33248170
http://dx.doi.org/10.1016/j.jhep.2020.11.024
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