| Title: |
Rare Atg7 Genetic Variants Predispose to Severe Fatty Liver Disease |
| Authors: |
Baselli, G.; Pelusi, S.; Ciociola, E.; Dongiovanni, P.; Maggioni, M.; Bianco, C.; Tavaglione, F.; Cespiati, A.; Mancina, R. M.; Malvestiti, F.; Costanza, J.; D?Ambrosio, R.; Petta, S.; Miele, L.; Gentilucci, U. V.; Federico, A.; Pihlajamaki, J.; Bugianesi, E.; Fracanzani, A. L.; Reeves, H.; Soardo, G.; Prati, D.; Romeo, S.; Valenti, L. |
| Contributors: |
G. Baselli; S. Pelusi; E. Ciociola; P. Dongiovanni; M. Maggioni; C. Bianco; F. Tavaglione; A. Cespiati; R.M. Mancina; F. Malvestiti; J. Costanza; R. D?ambrosio; S. Petta; L. Miele; U.V. Gentilucci; A. Federico; J. Pihlajamaki; E. Bugianesi; A.L. Fracanzani; H. Reeve; G. Soardo; D. Prati; S. Romeo; L. Valenti |
| Publisher Information: |
Elsevier |
| Publication Year: |
2022 |
| Collection: |
The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: |
Settore BIOS-14/A - Genetica |
| Description: |
Background&Aims: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and has a strong heritable component. The aim of this study was to identify new genes involved in NAFLD pathogenesis. Methods: We examined rare variants captured by whole-exome sequencing in individuals with severe fibrosis or hepatocellular carcinoma due to NAFLD (severe NAFLD, n=301) after variant prioritization. We replicated the results in the UK Biobank and the Liver biopsy cohort (n=2268). Results: We observed an enrichment of the p.P426L variant (rs143545741 C>T; OR=7.2, 2.3-17.3; pC; MAF=0.060 vs. 0.035; OR=1.7, 1.2-2.5; p=0.003). In the UK Biobank cohort, the p.V471A variant was associated with NAFLD (p=0.009) and liver disorders (p=0.004). In the Liver biopsy cohort, the p.V471A variant was linked with severe fibrosis, particularly in those with severe steatosis (p=0.002). Moreover, p.V471A was an independent predictor of hepatocellular ballooning (p=0.007). Hepatic ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers (n=125 with available transcriptomic). ATG7 protein localized to non-parenchymal cells and predominantly in periportal hepatocytes, more so in the presence of ballooning. Finally, we confirmed that in vitro the p.P426L and p.V471A variants result in a protein loss-of-function. Conclusion: We identified novel rare and low-frequency ATG7 variants contributing to severe NAFLD. The underlying mechanism may involve impairment of autophagy and facilitation of hepatocellular ballooning degeneration. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
volume:77; firstpage:596; lastpage:606; numberofpages:11; journal:JOURNAL OF HEPATOLOGY; https://hdl.handle.net/2434/1209956 |
| DOI: |
10.2139/ssrn.3806074 |
| Availability: |
https://hdl.handle.net/2434/1209956; https://doi.org/10.2139/ssrn.3806074 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.A00FDF59 |
| Database: |
BASE |