Rare gene variants may increase risk for severe NAFLD in obesity
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Severe nonalcoholic fatty liver disease may be correlated with Autophagy Related Gene 7 loss-of-function variants, which may impair hepatocellular ballooning and inflammation.
“We feel that the impaired ATG7 activity and autophagy are involved in pathogenesis of steatohepatitis in individuals with fatty liver disease,” Cristiana Bianco, MD, from Translational Medicine-department of transfusion medicine and Hematology-Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, said at the Digital NAFLD Summit 2021. “Rare ATG7 variants are enriched in patients with severe and in particular loss-of-function variants associated with liver injury and hepatocellular carcinoma.”
Bianco and colleagues conducted whole-exome sequencing in 301 European patients with NAFLD, advanced fibrosis and/or HCC. Then, investigators performed variant prioritization on in silico predictors and identified variants enriched population compared with the general population (GnomAD Non-Finnish Europeans and UK Biobank cohort [UKBB] without liver disease, n = 180,391). They also conducted validation at the gene level.
Researchers investigated the molecular mechanisms in a Liver Transcriptomic Cohort (LTC) of 125 obese patients after replicating the results in the European Liver Biopsy Cohort (LBC n = 2,268) and the UKBB.
Investigators noted an enrichment of the p.P426L variant (OR = 5.26, 95% CI, 2.06-12.61) of ATG7 in the severe NAFLD cohort compared with the general population, which researchers characterized as a loss-function. Bianco and colleagues noted a higher burden of rare (OR = 13.9; 95% CI, 1.9-611) in the conserved C-terminal ATG7 domain. In addition, there was an increased frequency of the p.V471A variant (minor allele frequency = 0.06 vs. 0.035; OR = 1.7, 95% CI, 1.2-2.5).
According to results in the UKBB, loss-of-function ATG7 variants correlated with an increased risk for cirrhosis (OR = 3.3; 95% CI, 1.1-7.5) and HCC (OR = 12.3, 95% CI, 2.6-36; P < .001 for both).
“In keeping with gene variant interaction, we also found an association with HCC only in severely obese individuals,” Bianco said. “[In] the Liver Biopsy Cohort we found that the p.V471A variant was not associated with steatosis but was an independent predictor of ballooning degeneration.”
Results from the liver biopsy cohort showed a correlation between p.V471A and severe fibrosis in patients with severe steatosis (P = .002). Bianco and colleagues noted p.V471A was an independent predictor for hepatocellular ballooning (P = .007).
There was correlation between ATG7 and suppression of the TNF-alpha pathway in the liver transcriptomic cohort. Bianco and colleagues noted this conversely was upregulated in carriers of p.V471A.
She said the ATG7 protein was expressed outside the lipid droplets and staining intensity was higher in patients with hepatocellular ballooning.
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Baselli G, et al. Abstract: OS-185. Presented at: EASL NAFLD Summit; Sept. 16-17, 2021 (virtual meeting).
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