| 1. |
- Baselli, Guido A, et al.
(författare)
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Rare ATG7 genetic variants predispose patients to severe fatty liver disease.
- 2022
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 77:3, s. 596-606
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Tidskriftsartikel (refereegranskat)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, Christina, et al.
(författare)
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Genetic risk scores and personalization of care in fatty liver disease.
- 2021
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Ingår i: Current opinion in pharmacology. - : Elsevier BV. - 1471-4973 .- 1471-4892. ; 61, s. 6-11
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver diseaseis the leading cause of chronic liver disease. Genetic predisposition, lifestyle, and metabolic comorbidities concur to nonalcoholic fatty liver disease development and progression to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Improvement in risk stratification and development of effective therapies for nonalcoholic steatohepatitis are key unmet clinical needs. Knowledge emerging from genomics could meet this need. A polygenic risk score (PRS) is calculated by summing the number of trait-associated alleles carried by an individual, which can be weighted by their effectsize on the trait and captures the individual's genetic risk to develop a disease. In this review, we focalize on the potential use of PRSs for disease detection at an early stage and stratification of the risk of progression to severe forms. PRSs may represent robust instruments to implement targeted prevention programs, hepatocellular carcinoma surveillance in at-risk individuals, and to develop precision medicine therapeutic approaches.
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| 3. |
- Bianco, Cristiana, et al.
(författare)
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Predictors of controlled attenuation parameter in metabolic dysfunction
- 2024
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Ingår i: United European Gastroenterology Journal. - 2050-6406 .- 2050-6414. ; 12:3, s. 364-373
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Hepatic fat content can be non-invasively estimated by controlled attenuation parameter (CAP) during transient elastography. The aim of this study was to examine the determinants and predictors of CAP values in individuals with metabolic dysfunction. Methods: We enrolled 1230 consecutive apparently healthy individuals (Liver-Bible-2022 cohort) with ≥3 metabolic dysfunction features. CAP was measured by Fibroscan. CAP determinants and predictors were identified using backward stepwise analysis and introduced in generalized linear models. Results: Participants were predominantly males (82.9%), mean age was 53.8±6.4years, 600 (48.8%) had steatosis (CAP≥275dB/m), and 27 had liver stiffness measurement (LSM)≥8kPa. CAP values correlated with LSM (p<10−22). In multivariable analysis, fasting insulin and abdominal circumference (AC) were the main determinants of CAP (p<10−6), together with body mass index (BMI; p<10−4), age, diabetes, triglycerides, ferritin, and lower HDL and thyroid stimulating hormone (TSH; p<0.05 for all). In a subset of 592 participants with thyroid hormone measurement, we found an association between higher free triiodothyronine levels, correlating with lower TSH, and CAP values, independent of TSH and of levothyroxine treatment (p=0.0025). A clinical CAP score based on age, BMI, AC, HbA1c, ALT, and HDL predicted CAP≥275dB/m with moderate accuracy (AUROC=0.73), which was better than that of the Fatty Liver Index and of ALT (AUROC=0.70/0.61, respectively) and validated it in multiple cohorts. Conclusion: Abdominal adiposity and insulin resistance severity were the main determinants of CAP in individuals with metabolic dysfunction and may improve steatotic liver disease risk stratification. CAP values were modulated by the hypophysis-thyroid axis.
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| 4. |
- De Vincentis, Antonio, et al.
(författare)
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A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores.
- 2022
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Ingår i: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. - : Elsevier BV. - 1542-7714. ; 20:3, s. 658-673
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Tidskriftsartikel (refereegranskat)abstract
- A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7 and GCKR predicts hepatic fat content (PRS-HFC). Here we hypothesize that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD).We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma and/or liver transplantation during a median follow-up of 9 years. NAFLD fibrosis score (NFS), FIB-4, APRI, BARD and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity and positive fatty liver index (FLI≥60).Unfavorable genetics (PRS-HFC≥0.396) further stratified the risk of SLD in subjects in intermediate/high risk classes of fibrosis scores, with higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (AUROCs increased for all scores with p∼10-2-10-4, except for APRI in the overall population and in subjects with obesity. PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not/poorly affected by unfavorable genetics in subjects without metabolic risk factors.Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for NAFLD. These data provide first evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.
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| 5. |
- De Vincentis, Antonio, et al.
(författare)
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Genetic variants in the MTHFR are not associated with fatty liver disease.
- 2020
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Ingår i: Liver international : official journal of the International Association for the Study of the Liver. - : Wiley. - 1478-3231. ; 40:8, s. 1934-1940
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Tidskriftsartikel (refereegranskat)abstract
- The common missense sequence variants of methylenetetrahydrofolate-reductase (MTHFR), rs1801131 (c.A1298C) and rs1801133 (c.C677T), favor the development of hyperhomocysteinemia and diminished DNA methylation. Previous studies, carried out in small series and with suboptimal characterization of the hepatic phenotype, tested the association of these genetic variants with fatty liver disease (FLD), with conflicting results. Here, we assessed the association of rs1801131 and rs1801133 with hepatic phenotype in the Liver Biopsy Cross-Sectional Cohort, a large cohort (n=1375 from Italy and 411 from Finland) of European individuals with suspect FLD associated with dysmetabolism. A total of 1786 subjects were analyzed by ordinal regression analyses. The rs1801131 and the rs1801133 variants were not associated with steatosis, inflammation, ballooning, or fibrosis. The present study suggests that changes in folate and methionine metabolism resulting from these 2 variants are not associated with a clinically significant impact on FLD in Europeans.
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| 6. |
- De Vincentis, A., et al.
(författare)
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Metabolic and genetic determinants for progression to severe liver disease in subjects with obesity from the UK Biobank
- 2022
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 46, s. 486-493
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Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is among the main determinants of nonalcoholic fatty liver disease progression towards severe liver disease (SLD). However, risk factors for SLD in individuals with obesity have not been examined. Objectives To identify the independent risk factors for SLD among participants with obesity from the UK Biobank. Methods A total of 80,224 UK Biobank participants with obesity (body mass index[BMI] > 30 kg/m(2)) and 242,822 without obesity, of European descent without clinical history of liver disease and liver cancer were prospectively followed for the onset of SLD, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma and/or liver transplantation. Risk factors for incident SLD were assessed by Cox proportional hazards models. Different clinical phenotypes were derived by latent class analysis (LCA). Results Obesity conferred a 2.6-fold increased risk for SLD that was abolished after the inclusion of waist circumference (WC) in the model. Among individuals with obesity, age (adjusted hazard ratio [aHR] 1.05, 95%CI 1.03-1.07, p = 3.9 * 10(-7)), type 2 diabetes (aHR 2.18, 95%CI 1.55-3.05, p = 6.2 * 10(-6)), PNPLA3 rs738409 (aHR 1.59, 95%CI 1.33-1.9, p = 3.1 * 10(-7)) and WC (aHR 1.04, 95%CI 1.02-1.06, p = 8.5 * 10(-6)) were independent predictors of SLD. BMI category-specific WC thresholds allowed a better risk stratification compared to traditional ones. By LCA, the clinical phenotype at highest risk for SLD was that with BMI < 35 kg/m(2) and WC above BMI-category specific thresholds. Conclusions Age, WC, type 2 diabetes, and the PNPLA3 variant are the main risk factors for SLD in individuals with obesity. WC is the principal mediator of SLD risk conveyed by increased BMI. BMI category-specific WC-thresholds may refine the SLD risk more accurately than traditional thresholds.
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| 7. |
- De Vincentis, Antonio, et al.
(författare)
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Poor accuracy and sustainability of the first-step FIB4 EASL pathway for stratifying steatotic liver disease risk in the general population.
- 2024
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Ingår i: Alimentary pharmacology & therapeutics. - 1365-2036.
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Tidskriftsartikel (refereegranskat)abstract
- The European Association for the Study of the Liver introduced a clinical pathway (EASL CP) for screening significant/advanced fibrosis in people at risk of steatotic liver disease (SLD). We assessed the performance of the first-step FIB4 EASL CP in the general population across different SLD risk groups (MASLD, Met-ALD and ALD) and various age classes.We analysed a total of 3372 individuals at risk of SLD from the 2017-2018 National Health and Nutrition Examination Survey (NHANES17-18), projected to 152.3million U.S. adults, 300,329 from the UK Biobank (UKBB) and 57,644 from the Biobank Japan (BBJ). We assessed liver stiffness measurement (LSM) ≥8kPa and liver-related events occurring within 3 and 10years (3/10year-LREs) as outcomes. We defined MASLD, MetALD, and ALD according to recent international recommendations.FIB4 sensitivity for LSM≥8kPa was low (27.7%), but it ranged approximately 80%-90% for 3-year LREs. Using FIB4, 22%-57% of subjects across the three cohorts were identified as candidates for vibration-controlled transient elastography (VCTE), which was mostly avoidable (positive predictive value of FIB4≥1.3 for LSM≥8kPa ranging 9.5%-13% across different SLD categories). Sensitivity for LSM≥8kPa and LREs increased with increasing alcohol intake (ALD>MetALD>MASLD) and age classes. For individuals aged ≥65years, using the recommended age-adjusted FIB4 cut-off (≥2) substantially reduced sensitivity for LSM≥8kPa and LREs.The first-step FIB4 EASL CP is poorly accurate and feasible for individuals at risk of SLD in the general population. It is crucial to enhance the screening strategy with a first-step approach able to reduce unnecessary VCTEs and optimise their yield.
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| 8. |
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| 9. |
- Holmer, Magnus, et al.
(författare)
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Effect of common genetic variants on the risk of cirrhosis in non-alcoholic fatty liver disease during 20 years of follow-up
- 2022
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Ingår i: Liver international (Print). - : Wiley. - 1478-3223 .- 1478-3231. ; 42:12, s. 2769-2780
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims Several genotypes associate with a worse histopathological profile in patients with non-alcoholic fatty liver disease (NAFLD). Whether genotypes impact long-term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD. Method DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non-alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population-based registers. Events of severe liver disease and all-cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression. Results In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66-8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79-4.14). After up to 40 years of follow-up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15-4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85-11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14-59.47). Overall mortality was not affected by any genetic variant. Conclusion The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies.
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| 10. |
- Hutchison, Alan L, et al.
(författare)
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Endocrine aspects of metabolic dysfunction associated steatotic liver disease (MASLD): Beyond insulin resistance.
- 2023
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Ingår i: Journal of hepatology. - 1600-0641. ; 79:6, s. 1524-1541
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Tidskriftsartikel (refereegranskat)abstract
- While the links between metabolic dysfunction associated steatotic liver disease liver disease (MASLD) and obesity, insulin resistance are widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of direct and indirect specific endocrine dysregulation and severity of MASLD. Strong evidence of direct and indirect effects exists for low levels of growth hormone, sex hormones, and thyroid hormone with development and severity of disease. The impact of steroid hormones, e.g. cortisol and dehydropepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and also of management of non-insulin endocrine axes should be performed in the evaluation and management of MASLD. Multiple therapeutic pharmaceutical targets have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in metabolic dysfunction associated steatohepatitis (MASH).
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