NAFLD is most frequently linked to excess adiposity, insulin resistance and cardiometabolic risk factors, it has become the leading cause of liver disease worldwide, and is associated with increased mortality due to multiple causes. HFC has a strong genetic component and the investigators recently showed that it plays a causal role in determining progressive liver disease and insulin resistance. The genetic risk score predicting liver fat content (HFC-GRS) improves the stratification of liver related events, and the investigators have preliminary data on new common and rare variants that contribute to NAFLD susceptibility, and on a new non-invasive circulating biomarker associated with hepatic fat and lipotoxicity (Interleukin-32). However, no data are yet available on the causal role of hepatic fat on the procoagulant state associated with NAFLD, which could participate to liver damage and is a causal factor in atherothrombotic complications. The aim of the study is to examine the potential application of a precision medicine approach to the improvement of stratification of the risk of liver-related and cardiovascular thrombotic complications of hepatic fat accumulation (HFC) and non-alcoholic fatty liver disease (NAFLD), with a special focus on the role of procoagulant imbalance in mediating the at-risk phenotypes.
The aims of the project will be: * To examine whether a comprehensive HFC-GRS coupled with evaluation of environmental triggers, imaging techniques and novel circulating biomarkers help in stratifying of the risk of NAFLD and associated complications in a cohort of asymptomatic individuals at high risk from the general population (the Liver-Bible cohort). The Liver-Bible cohort is made up of \>2,500 individuals with multiple metabolic risk factors, who are undergoing a comprehensive evaluation of environmental exposure, HFC and liver stiffness measurement, liver histology in those at risk of advanced fibrosis, circulating biomarkers of hepatic damage, coagulation status and early cardiovascular damage; * To validate the causal role of HFC in the alterations of metabolism, coagulation, and early cardiovascular damage associated with NAFLD; * To identify new inherited risk variants and microbiota profiles associated with NAFLD; to investigate the mechanism linking genetic susceptibility with liver disease and coagulation balance in in vitro models of NAFLD in hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells. The investigators expect to demonstrate that the combined evaluation of genetic and novel circulating biomarkers with imaging improves the non-invasive prediction of both liver-related (leading to personalised and cost-effective surveillance of liver-related complications) and unrelated complications of NAFLD in at risk individuals, with a special focus on the role of the coagulation balance, and to pinpoint new genetic modifiers of disease progression that may be prioritized for future therapeutic approaches.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
PREVENTION
Masking
NONE
Enrollment
2,500
precision medicine approach to improvement of risk stratification of hepatic and cardiovascular complications in non-alcoholic fatty liver disease in a group of healthy subjects at increased risk of metabolic pathologies
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica
Milan, Milano, Italy
RECRUITINGassociation of liver fat accumulation
At the time of enrollment, to test the association of liver fat accumulation (HFC) with liver disease and cardiovascular complications the association between HFC-genetic risk score (GRS) data will be collected on the characterization of clinical risk factors through Fibroscan measurement of liver stiffness, liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), in subjects at higher metabolic risk and therefore dysteatosis. This information will be collected in the blood donor subject's management system.
Time frame: up to 48 months
the role of liver fat
The genetic risk score predicts liver fat content (HFC-GRS) can improve risk stratification of liver disease progression in NAFLD and how new common and rare genetic variants contribute to susceptibility to NAFLD. The same data also highlighted a possible new non-invasive circulating biomarker associated with liver fat and lipotoxicity (interleukin-32). So the evaluation of complete genetic risk scores (GRS) can be used to stratify the risk of liver-related complications and to select the best pharmacological therapy. Technological advances that enable the interrogation of the entire human genome, combined with the exploitation of bioinformatics systems approaches, are proving promising for providing patients and clinicians with unique health information from the molecular, cellular to multi-organ levels. By taking advantage of these new technologies, we assessed the role of liver fat (HFC) in coagulation alterations and influence cardiovascular risk.
Time frame: up to 48 months
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