| 1. |
- Baselli, Guido A, et al.
(author)
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Rare ATG7 genetic variants predispose patients to severe fatty liver disease.
- 2022
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In: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 77:3, s. 596-606
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Journal article (peer-reviewed)abstract
- 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.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.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.We identified rare and low-frequency ATG7 loss-of-function variants as modifiers of NAFLD progression by impairing autophagy and facilitating ballooning and inflammation.•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.
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| 2. |
- Bianco, Cristina, et al.
(author)
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Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
- 2021
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In: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 74:4, s. 775-782
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Journal article (peer-reviewed)abstract
- Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification.We examined at-risk individuals (NAFLD cohort, n=2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n=364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5).In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p=0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p<10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p<0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p<10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ∼90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p<10-5) and without cirrhosis (p<0.05).Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy to detect HCC and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings.
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| 3. |
- Donati, Benedetta, et al.
(author)
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Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.
- 2017
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In: Cancer medicine. - : Wiley. - 2045-7634. ; 6:8, s. 1930-1940
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Journal article (peer-reviewed)abstract
- In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in patients with nonalcoholic fatty liver disease (NAFLD). Mutations in telomerase reverse transcriptase (hTERT) are associated with familial liver diseases. The aim of this study was to examine telomere length and germline hTERT mutations as associated with NAFLD-HCC. In 40 patients with NAFLD-HCC, 45 with NAFLD-cirrhosis and 64 healthy controls, peripheral blood telomere length was evaluated by qRT-PCR and hTERT coding regions and intron-exon boundaries sequenced. We further analyzed 78 patients affected by primary liver cancer (NAFLD-PLC, 76 with HCC). Enrichment of rare coding mutations (allelic frequency <0.001) was evaluated by Burden test. Functional consequences were estimated in silico and by over-expressing protein variants in HEK-293 cells. We found that telomere length was reduced in individuals with NAFLD-HCC versus those with cirrhosis (P=0.048) and healthy controls (P=0.0006), independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD-HCC, that was confirmed when we further considered a larger cohort of NAFLD-PLC, and was more marked in female patients (P=0.03). No mutations were found in cirrhosis and local controls, and only one in 503 healthy Europeans from the 1000 Genomes Project (allelic frequency=0.025 vs. <0.001; P=0.0005). Mutations with predicted functional impact, including the frameshift Glu113Argfs*79 and missense Glu668Asp, cosegregated with liver disease in two families. Three patients carried missense mutations (Ala67Val in homozygosity, Pro193Leu and His296Pro in heterozygosity) in the N-terminal template-binding domain (P=0.037 for specific enrichment). Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels. In conclusion, we detected an association between shorter telomeres in peripheral blood and rare germline hTERT mutations and NAFLD-HCC.
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| 4. |
- Dongiovanni, Paola, et al.
(author)
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Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease.
- 2018
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In: Hepatology communications. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 2:6, s. 666-675
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Journal article (peer-reviewed)abstract
- Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42-0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95% CI, 0.14-0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95% CI, 0.07-0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10-8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down-regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666-675).
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| 5. |
- Pelusi, Serena, et al.
(author)
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Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Journal article (peer-reviewed)abstract
- Nonalcoholic fatty liver disease (NAFLD) is a rising cause of hepatocellular carcinoma (HCC). We examined whether inherited pathogenic variants in candidate genes (n=181) were enriched in patients with NAFLD-HCC. To this end, we resequenced peripheral blood DNA of 142 NAFLD-HCC, 59 NAFLD with advanced fibrosis, and 50 controls, and considered 404 healthy individuals from 1000G. Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. In NAFLD-HCC patients, we detected an enrichment in pathogenic (p=0.024), and likely pathogenic variants (p=1.9*10-6), particularly in APOB (p=0.047). APOB variants were associated with lower circulating triglycerides and higher HDL cholesterol (p<0.01). A genetic risk score predicted NAFLD-HCC (OR 4.96, 3.29-7.55; p=5.1*10-16), outperforming the diagnostic accuracy of common genetic risk variants, and of clinical risk factors (p<0.05). In conclusion, rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development.
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| 6. |
- Qadri, Sami, et al.
(author)
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Obesity Modifies the Performance of Fibrosis Biomarkers in Nonalcoholic Fatty Liver Disease
- 2022
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In: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 107:5, s. e2008-e2020
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Journal article (peer-reviewed)abstract
- Context: Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. Objective: To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. Design: Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3). Setting: Tertiary referral center. Patients: We recruited overweight/obese patients from endocrinology (n = 307) and hepatology (n = 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m(2)]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS. Main Outcome Measures: Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage >= F3 fibrosis or nonalcoholic steatohepatitis with >= F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]. Results: The scores with an AUROC >= 0.85 to identify >= F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out >= F3 fibrosis in groups with BM Is <30.0, 30.0 to 39.9, and >= 40.0 kg/m(2). This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose >= F3 fibrosis. Conclusions: In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cutoffs.
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