A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores

Antonio De Vincentis; Federica Tavaglione; Oveis Jamialahmadi; Antonio Picardi; Raffaele Antonelli Incalzi; Luca Valenti; Stefano Romeo; Umberto Vespasiani-Gentilucci

doi:10.1016/j.cgh.2021.05.056

A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores

Clin Gastroenterol Hepatol. 2022 Mar;20(3):658-673. doi: 10.1016/j.cgh.2021.05.056. Epub 2021 Jun 4.

Authors

Antonio De Vincentis¹, Federica Tavaglione², Oveis Jamialahmadi³, Antonio Picardi⁴, Raffaele Antonelli Incalzi⁵, Luca Valenti⁶, Stefano Romeo⁷, Umberto Vespasiani-Gentilucci⁸

Affiliations

¹ Internal Medicine Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy; Internal Medicine, Saint Camillus International University of Health and Medical Sciences, Rome, Italy.
² Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy; Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁴ Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy.
⁵ Internal Medicine Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy.
⁶ Department of Pathophysiology and Transplantation, Università; degli Studi di Milano, Milano, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
⁷ Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Science, Magna Graecia University, Catanzaro, Italy; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁸ Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy. Electronic address: u.vespasiani@unicampus.it.

PMID: 34091049
DOI: 10.1016/j.cgh.2021.05.056

Abstract

Background & aims: A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD).

Methods: We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60).

Results: Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10^-2 to 10^-4, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors.

Conclusions: Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.

Keywords: Genetics; Nonalcoholic Fatty Liver Disease (NAFLD); PNPLA3; UK Biobank.

Publication types

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

MeSH terms

Fibrosis
Humans
Liver / pathology
Liver Cirrhosis / diagnosis
Liver Neoplasms* / pathology
Non-alcoholic Fatty Liver Disease* / epidemiology
Prospective Studies
Risk Assessment
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding