| Přispěvatelé: |
Baselli, Guido A, Jamialahmadi, Ovei, Pelusi, Serena, Ciociola, Ester, Malvestiti, Francesco, Saracino, Marco, Santoro, Luigi, Cherubini, Alessandro, Dongiovanni, Paola, Maggioni, Marco, Bianco, Cristiana, Tavaglione, Federica, Cespiati, Annalisa, Mancina, Rosellina M, D'Ambrosio, Roberta, Vaira, Valentina, Petta, Salvatore, Miele, Luca, Vespasiani-Gentilucci, Umberto, Federico, Alessandro, Pihlajamaki, Jussi, Bugianesi, Elisabetta, Fracanzani, Anna L, Reeves, Helen L, Soardo, Giorgio, Prati, Daniele, Romeo, Stefano, Valenti, Luca Vc |
| Popis: |
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 in-dividuals 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; 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 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 |
