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Lookup NU author(s): Dr Luca Miele,
Professor Helen ReevesORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2022 The Authors. Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. Methods: We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. Results: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; OR 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in a Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. Conclusions: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. Lay summary: We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation.
Author(s): Baselli GA, Jamialahmadi O, Pelusi S, Ciociola E, Malvestiti F, Saracino M, Santoro L, Cherubini A, Dongiovanni P, Maggioni M, Bianco C, Tavaglione F, Cespiati A, Mancina RM, D'Ambrosio R, Vaira V, Petta S, Miele L, Vespasiani-Gentilucci U, Federico A, Pihlajamaki J, Bugianesi E, Fracanzani AL, Reeves HL, Soardo G, Prati D, Romeo S, Valenti LV, Borroni V, Liguori A, Ronzoni L, Tomasi M, Lombardi A, Ostadreza M, Casirati E, Marini I, Maier S, Rosso C, Baroni GS, Santaniello C, Dallio M
Publication type: Article
Publication status: Published
Journal: Journal of Hepatology
Print publication date: 01/09/2022
Online publication date: 09/04/2022
Acceptance date: 15/03/2022
Date deposited: 24/05/2022
ISSN (print): 0168-8278
ISSN (electronic): 1600-0641
Publisher: Elsevier B.V.
PubMed id: 35405176
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