| Title: | Rare ATG7 genetic variants predispose patients to severe fatty liver disease |
| Journal: | Journal of Hepatology |
| Published: | 9 Apr 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35405176/ |
| DOI: | https://doi.org/10.1016/j.jhep.2022.03.031 |
| URL: | http://www.journal-of-hepatology.eu/article/S0168827822002070/pdf |
| Citations: | 49 (35 in last 2 years) as of 8 Aug 2024 |
Publication 12418
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Abstract
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.</p>
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.</p>
RESULTS: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [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 the 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.</p>
CONCLUSIONS: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation.</p>
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.</p>
9 Keywords
- Autophagy-Related Protein 7
- Biopsy
- Carcinoma, Hepatocellular
- Humans
- Inflammation
- Liver
- Liver Cirrhosis
- Liver Neoplasms
- Non-alcoholic Fatty Liver Disease
44 Authors
- Guido A. Baselli
- Oveis Jamialahmadi
- Serena Pelusi
- Ester Ciociola
- Francesco Malvestiti
- Marco Saracino
- Luigi Santoro
- Alessandro Cherubini
- Paola Dongiovanni
- Marco Maggioni
- Cristiana Bianco
- Federica Tavaglione
- Annalisa Cespiati
- Rosellina M. Mancina
- Roberta D'Ambrosio
- Valentina Vaira
- Salvatore Petta
- Luca Miele
- Umberto Vespasiani-Gentilucci
- Alessandro Federico
- Jussi Pihlajamaki
- Elisabetta Bugianesi
- Anna L. Fracanzani
- Helen L. Reeves
- Giorgio Soardo
- Daniele Prati
- Stefano Romeo
- Luca VC. Valenti
- EPIDEMIC Study Investigators
- Vittorio Borroni
- Antonio Liguori
- Luisa Ronzoni
- Alessandro Cherubini
- Luigi Santoro
- Melissa Tomasi
- Angela Lombardi
- Mahnoosh Ostadreza
- Elia Casirati
- Ilaria Marini
- Silvia Maier
- Chiara Rosso
- Gianluca Svegliati Baroni
- Carlo Santaniello
- Marcello Dallio
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