Data di Pubblicazione:
2022
Citazione:
Rare ATG7 genetic variants predispose patients to severe fatty liver disease / G.A. Baselli, O. Jamialahmadi, S. Pelusi, E. Ciociola, F. Malvestiti, M. Saracino, L. Santoro, A. Cherubini, P. Dongiovanni, M. Maggioni, C. Bianco, F. Tavaglione, A. Cespiati, R.M. Mancina, R. D'Ambrosio, V. Vaira, S. Petta, L. Miele, U. Vespasiani-Gentilucci, A. Federico, J. Pihlajamaki, E. Bugianesi, A.L. Fracanzani, H.L. Reeves, G. Soardo, D. Prati, S. Romeo, L.V. Valenti. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 77:3(2022 Sep), pp. 596-606. [10.1016/j.jhep.2022.03.031]
Abstract:
Background & aims: Nonalcoholic 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 contributing 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, followed by validation at gene level. Results: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; OR 5.26, 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, 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, 1.1-7.5 and OR 12.30, 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, 1.2-2.5; p=0.003), predisposed to hepatocellular ballooning (p=0.007) evolving to fibrosis in a Liver biopsy cohort (n=2268), and was associated with liver injury in the UK Biobank (AST levels, p<0.001), with a larger effect in severely obese individuals where it was linked to hepatocellular carcinoma (p=0.009). ATG7 protein localized to periportal hepatocytes, more so 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 as modifiers of NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. Lay summary: •We found that rare mutations in a gene called autophagy related (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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
NAFLD; NASH; autophagy; genetics; liver fibrosis;
Elenco autori:
G.A. Baselli, O. Jamialahmadi, S. Pelusi, E. Ciociola, F. Malvestiti, M. Saracino, L. Santoro, A. Cherubini, P. Dongiovanni, M. Maggioni, C. Bianco, F. Tavaglione, A. Cespiati, R.M. Mancina, R. D'Ambrosio, V. Vaira, S. Petta, L. Miele, U. Vespasiani-Gentilucci, A. Federico, J. Pihlajamaki, E. Bugianesi, A.L. Fracanzani, H.L. Reeves, G. Soardo, D. Prati, S. Romeo, L.V. Valenti
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