The ‘EPoS European NAFLD Registry’ database and Biobank have been generated with both historic datasets and prospectively recruited patients with longitudinal follow-up to determine natural history and disease outcomes.
Our completed GWAS is the largest worldwide to date on histologically characterised NAFLD patients that addresses the full disease spectrum and is the first reporting the four gene combination of PNPLA3, TM6SF2, GCKR and HSD17B13 as NAFLD risk modifiers. In the case of our transcriptomic analysis by RNA sequencing, a set of 25 genes have been shown to change in expression as NAFLD progresses and our replication analysis has confirmed these changes for 84% of the gene set.
Multi-omics profiling has been performed, including shotgun metagenomics (gut microbiome), genetics, RNA sequencing (liver biopsies), and metabolomics/lipidomics (serum). Integrative analyses included generation of partial correlation network, integrating multi-omics variables together with relevant clinical variables and NAFLD scores. This analysis identified the variables which directly associate with NAFLD scores, and which allowed the identification of multi-omic biomarkers of NAFLD. Additionally, genome-scale metabolic modelling was applied, which identified the key metabolic pathways associated with specific NAFLD groups and also predicted which metabolites were produced or taken up by the liver. These metabolites were verified in patient-matched serum samples.
The results of the gut microbiome analyses highlighted signatures of the gut microbiota tied to liver pathology and fibrosis as well as elucidating the interplay with common co-morbidities.
In subjects with NAFLD, both hepatic insulin resistance and adipose tissue insulin resistance increase with BMI and the degree of liver fibrosis, while muscle insulin sensitivity (OGIS index) is decreased. Moreover, insulin secretion is altered in NAFLD, i.e. increased with both BMI and degree of liver fibrosis, while hepatic insulin clearance is decreased more in subjects with NASH and moderate to severe fibrosis (F2-F4).
The CONSTANS study has been concluded which has provided novel initial insight into healthcare trends and burden within outpatient hepatology clinics throughout western Europe.
Our research on animal models has provided evidence of the relevance of: a) MBOAT7 mediating the remodelling of phosphatidylinositols for liver disease and, more specifically, its effect on inflammatory responses; and b) PEPD, a gene involved in the balance between degradation/remodelling of collagen and its contribution to fibro-inflammation, both important stages in the natural evolution from NAFL to NASH. We have shown that specific dietary interventions leading to fatty liver in murine models, differentially affect the overall phenotype and the severity of liver damage caused by the primary genetic manipulation of MBOAT7 and PEPD genetic models.
Dissemination activities have been excellent, with 66 peer-reviewed journal papers published so far and numerous others in preparation or planned. In addition, 150 conference presentations have been given as well as 38 conference posters.
