Rare ATG7 genetic variants predispose patients to severe fatty liver disease
- PMID: 35405176
- DOI: 10.1016/j.jhep.2022.03.031
Rare ATG7 genetic variants predispose patients to severe fatty liver disease
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.
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; 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.
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.
Keywords: NAFLD; NASH; autophagy; genetics; liver fibrosis.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Conflict of interest The authors declare that they have no conflict of interest relevant to the present study. LV has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics and Ionis Pharmaceuticals, and received research grants from Gilead. SR has served as a consultant for AstraZeneca, Celgene, Sanofi, Amgen, Akcea Therapeutics, Camp4, AMbys, Medacorp and Pfizer in the past 5 years, and received research grants from AstraZeneca, Sanofi and Amgen. Please refer to the accompanying ICMJE disclosure forms for further details.
Comment in
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Lack of hepatic autophagy promotes severity of liver injury but not steatosis.J Hepatol. 2022 Nov;77(5):1458-1459. doi: 10.1016/j.jhep.2022.05.015. Epub 2022 May 25. J Hepatol. 2022. PMID: 35643205 Free PMC article. No abstract available.
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Reply to: "Lack of hepatic autophagy promotes severity of liver injury but not steatosis": ATG7 genetic variants behave as fatty liver disease progression modifiers.J Hepatol. 2022 Nov;77(5):1459-1461. doi: 10.1016/j.jhep.2022.07.026. Epub 2022 Aug 17. J Hepatol. 2022. PMID: 35985546 No abstract available.
