A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores
Year: 2021
Type: article
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.
Institutions: Università Campus Bio-Medico, Saint Camillus International University of Health and Medical Sciences, Campus Bio Medico University Hospital, University of Gothenburg, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Sahlgrenska University Hospital, Magna Graecia University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,800
Funders: Amgen, AstraZeneca, Sanofi, Celgene, European Commission, Stiftelsen för Strategisk Forskning, VINNOVA, Ministero della Salute, Hjärt-Lungfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Fondazione Italiana per la Ricerca sul Cancro, Diabetesförbundet, Svenska Diabetesstiftelsen, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Novo Nordisk Fonden, Stiftelsen för Strategisk Forskning, Akebia Therapeutics, Medical Research Council
Awards: G1284571523, Liver Investigation: Testing Marker Utility in Steatohepatitis, G1719642171, Lipidome fingerprint and novel molecular pathways underlying non-alcoholic fatty liver disease, G2464784432, G2586995165, G2709560356, G298858806, G3015077885, G333560594, G4237868980, G5850737185, G6922932923
OpenAlex ID: W3170870179