| 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, Cristina, et al.
(författare)
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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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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 74:4, s. 775-782
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Tidskriftsartikel (refereegranskat)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. |
- 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. |
- Caddeo, Andrea, et al.
(författare)
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MBOAT7 is anchored to endomembranes by six transmembrane domains.
- 2019
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Ingår i: Journal of structural biology. - : Elsevier BV. - 1095-8657 .- 1047-8477. ; 206:3, s. 349-360
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Tidskriftsartikel (refereegranskat)abstract
- Membrane bound O-acyltransferase domain- containing 7 (MBOAT7, also known as LPIAT1) is a protein involved in the acyl chain remodeling of phospholipids via the Lands' cycle. The MBOAT7 is a susceptibility risk genetic locus for non-alcoholic fatty liver disease (NAFLD) and mental retardation. Although it has been shown that MBOAT7 is associated to membranes, the MBOAT7 topology remains unknown. To solve the topological organization of MBOAT7, we performed: A) solubilization of the total membrane fraction of cells overexpressing the recombinant MBOAT7-V5, which revealed MBOAT7 is an integral protein strongly attached to endomembranes; B) in silico analysis by using 22 computational methods, which predicted the number and localization of transmembrane domains of MBOAT7 with a range between 5 and 12; C) in vitro analysis of living cells transfected with GFP-tagged MBOAT7 full length and truncated forms, using a combination of Western Blotting, co-immunofluorescence and Fluorescence Protease Protection (FPP) assay; D) in vitro analysis of living cells transfected with FLAG-tagged MBOAT7 full length forms, using a combination of Western Blotting, selective membrane permeabilization followed by indirect immunofluorescence. All together, these data revealed that MBOAT7 is a multispanning transmembrane protein with six transmembrane domains. Based on our model, the predicted catalytic dyad of the protein, composed of the conserved asparagine in position 321 (Asn-321) and the preserved histidine in position 356 (His-356), has a lumenal localization. These data are compatible with the role of MBOAT7 in remodeling the acyl chain composition of endomembranes.
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| 5. |
- Chang, Yu-Wei, et al.
(författare)
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Neural network training with highly incomplete medical datasets
- 2022
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Ingår i: Machine Learning-Science and Technology. - : IOP Publishing. - 2632-2153. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- Neural network training and validation rely on the availability of large high-quality datasets. However, in many cases only incomplete datasets are available, particularly in health care applications, where each patient typically undergoes different clinical procedures or can drop out of a study. Since the data to train the neural networks need to be complete, most studies discard the incomplete datapoints, which reduces the size of the training data, or impute the missing features, which can lead to artifacts. Alas, both approaches are inadequate when a large portion of the data is missing. Here, we introduce GapNet, an alternative deep-learning training approach that can use highly incomplete datasets without overfitting or introducing artefacts. First, the dataset is split into subsets of samples containing all values for a certain cluster of features. Then, these subsets are used to train individual neural networks. Finally, this ensemble of neural networks is combined into a single neural network whose training is fine-tuned using all complete datapoints. Using two highly incomplete real-world medical datasets, we show that GapNet improves the identification of patients with underlying Alzheimer's disease pathology and of patients at risk of hospitalization due to Covid-19. Compared to commonly used imputation methods, this improvement suggests that GapNet can become a general tool to handle incomplete medical datasets.
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| 6. |
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| 7. |
- Cherubini, Alessandro, et al.
(författare)
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Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women.
- 2023
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Ingår i: Nature medicine. - 1546-170X. ; 29:10, s. 2643-55
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Tidskriftsartikel (refereegranskat)abstract
- Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3 p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P<10-10; advanced fibrosis/hepatocellular carcinoma, P=0.034) and in the general population (P<10-7 for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3 expression was higher in women than in men (P=0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3 was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3 enhancer and demonstrated via CRISPR-Cas9 genome editing that this sequence drives PNPLA3 p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3 p.I148M variant contributes to FLD in women.
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| 8. |
- 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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| 9. |
- Govaere, O., et al.
(författare)
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Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:5, s. 1001-1012
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. © 2021 The Authors
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| 10. |
- Jamialahmadi, Oveis, et al.
(författare)
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A benchmark-driven approach to reconstruct metabolic networks for studying cancer metabolism.
- 2019
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Ingår i: PLoS computational biology. - : Public Library of Science (PLoS). - 1553-7358. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- Genome-scale metabolic modeling has emerged as a promising way to study the metabolic alterations underlying cancer by identifying novel drug targets and biomarkers. To date, several computational methods have been developed to integrate high-throughput data with existing human metabolic reconstructions to generate context-specific cancer metabolic models. Despite a number of studies focusing on benchmarking the context-specific algorithms, no quantitative assessment has been made to compare the predictive performance of these methods. Here, we integrated various and different datasets used in previous works to design a quantitative platform to examine functional and consistency performance of several existing genome-scale cancer modeling approaches. Next, we used the results obtained here to develop a method for the reconstruction of context-specific metabolic models. We then compared the predictive power and consistency of networks generated by our method to other computational approaches investigated here. Our results showed a satisfactory performance of the developed method in most of the benchmarks. This benchmarking platform is of particular use in algorithm selection and assessing the performance of newly developed algorithms. More importantly, it can serve as guidelines for designing and developing new methods focusing on weaknesses and strengths of existing algorithms.
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| 11. |
- Jamialahmadi, Oveis, et al.
(författare)
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Cellular Genome-Scale Metabolic Modeling Identifies New Potential Drug Targets Against Hepatocellular Carcinoma.
- 2022
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Ingår i: Omics : a journal of integrative biology. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 26:12, s. 671-682
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Tidskriftsartikel (refereegranskat)abstract
- Genome-scale metabolic modeling (GEM) is one of the key approaches to unpack cancer metabolism and for discovery of new drug targets. In this study, we report the Transcriptional Regulated Flux Balance Analysis-CORE (TRFBA-), an algorithm for GEM using key growth-correlated reactions using hepatocellular carcinoma (HCC), an important global health burden, as a case study. We generated a HepG2 cell-specific GEM by integrating this cell line transcriptomic data with a generic human metabolic model to forecast potential drug targets for HCC. A total of 108 essential genes for growth were predicted by the TRFBA-CORE. These genes were enriched for metabolic pathways involved in cholesterol, sterol, and steroid biosynthesis. Furthermore, we silenced a predicted essential gene, 11-beta dehydrogenase hydroxysteroid type 2 (HSD11B2), in HepG2 cells resulting in a reduction in cell viability. To further identify novel potential drug targets in HCC, we examined the effect of nine drugs targeting the essential genes, and observed that most drugs inhibited the growth of HepG2 cells. Some of these drugs in this model performed better than Sorafenib, the first-line therapeutic against HCC. A HepG2 cell-specific GEM highlights sterol metabolism to be essential for cell growth. HSD11B2 downregulation results in lower cell growth. Most of the compounds, selected by drug repurposing approach, show a significant inhibitory effect on cell growth in a wide range of concentrations. These findings offer new molecular leads for drug discovery for hepatic cancer while also illustrating the importance of GEM and drug repurposing in cancer therapeutics innovation.
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| 12. |
- Mancina, Rosellina Margherita, et al.
(författare)
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PSD3 downregulation confers protection against fatty liver disease.
- 2022
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:1, s. 60-75
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Tidskriftsartikel (refereegranskat)abstract
- Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
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| 13. |
- Mijalkov, Mite, et al.
(författare)
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Sex differences in multilayer functional network topology over the course of aging in 37543 UK Biobank participants
- 2023
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Ingår i: Network Neuroscience. - : MIT Press. - 2472-1751. ; 7:1, s. 351-376
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Tidskriftsartikel (refereegranskat)abstract
- Aging is a major risk factor for cardiovascular and neurodegenerative disorders, with considerable societal and economic implications. Healthy aging is accompanied by changes in functional connectivity between and within resting-state functional networks, which have been associated with cognitive decline. However, there is no consensus on the impact of sex on these age-related functional trajectories. Here, we show that multilayer measures provide crucial information on the interaction between sex and age on network topology, allowing for better assessment of cognitive, structural, and cardiovascular risk factors that have been shown to differ between men and women, as well as providing additional insights into the genetic influences on changes in functional connectivity that occur during aging. In a large crosssectional sample of 37,543 individuals from the UK Biobank cohort, we demonstrate that such multilayer measures that capture the relationship between positive and negative connections are more sensitive to sex-related changes in the whole-brain connectivity patterns and their topological architecture throughout aging, when compared to standard connectivity and topological measures. Our findings indicate that multilayer measures contain previously unknown information on the relationship between sex and age, which opens up new avenues for research into functional brain connectivity in aging.
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| 14. |
- Oveis, Jamialahmadi, et al.
(författare)
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Exome-wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated with Fatty Liver Disease.
- 2021
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 160:5
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Tidskriftsartikel (refereegranskat)abstract
- Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered.To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase (ALT) at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8,930 participants in whom liver fat measurement was available, and replicated two genetic variants in three independent cohorts comprising 2,621 individuals with available liver biopsy.We identified 190 genetic variants independently associated with ALT after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver.We identified two novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
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| 15. |
- Oveis, Jamialahmadi, et al.
(författare)
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Fatty Liver Disease, Heart Rate, and Cardiac Remodelling: Evidence from the UK Biobank.
- 2023
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Ingår i: Liver international : official journal of the International Association for the Study of the Liver. - : Wiley. - 1478-3231. ; 43:6, s. 1247-1255
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Tidskriftsartikel (refereegranskat)abstract
- Growing evidence supports an association between fatty liver disease (FLD) and cardiac dysfunction and remodelling, leading to cardiovascular disease and heart failure. Herein, we investigated the independent contribution of FLD to cardiac dysfunction and remodelling in participants from the UK Biobank with cardiac magnetic resonance (CMR) data available.A total of 18,848 Europeans without chronic viral hepatitis and valvular heart diseases, with liver magnetic resonance imaging and CMR data were included in the analyses. Clinical, laboratory, and imaging data were collected using standardized procedures. Multivariable regression models were used to test the association between FLD and CMR endpoints, after adjusting for several cardiometabolic risk factors. Linear regression models with regularization (Least Absolute Shrinkage and Selection Operator [LASSO], Ridge, and Elastic Net) were used to generate predictive models for heart-related endpoints.FLD was independently associated with higher average heart rate, higher cardiac remodelling (higher eccentricity ratio and lower remodelling index), lower left and right ventricular volumes (end-systolic, end-diastolic, and stroke volumes) as well as with lower left and right atrial maximal volumes (P<0.001). FLD was the strongest positive predictor for average heart rate, followed by age, hypertension, and type 2 diabetes. Male sex was the strongest positive predictor for eccentricity ratio followed by FLD, age, hypertension, and BMI. For LV volumes, FLD was the strongest negative predictor along with age.FLD is an independent predictor of higher heart rate and early cardiac remodelling associated with reduced ventricular volumes.
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| 16. |
- Oveis, Jamialahmadi
(författare)
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Understanding the genetic architecture of fatty liver disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, ranging from simple steatosis to more severe conditions, namely non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD has a strong genetic component, and its heritability depends on environmental factors and ethnicity. So far, genome-wide association studies were able to explain only a small fraction of its heritability, indicating the presence of missing heritability. Moreover, despite more than 20% of the general population and more than 70% of individuals with obesity have fatty liver, only a minority of individuals will progress to end stage liver disease. In the first study, we used polygenic risk scores (PRS) based on 5 known common genetic determinants of NAFLD to stratify the risk of HCC in individuals with dysmetabolism. We showed the ability of our PRS to predict the full spectrum of NAFLD and HCC both in high-risk individuals and in the general population. Additionally, we demonstrated a causal association between genetic predisposition to hepatic steatosis and HCC using a Mendelian Randomization approach. In the second study, we performed an exome-wide association study of alanine aminotransferase (ALT), a biomarker of liver fat and damage, to identify other genetic determinants of fatty liver disease. We found two missense variants on GPAM and APOE genes, robustly associated with liver fat content and chronic liver disease. Finally, in the third study, we performed a gene-environment-wide interaction study (GEWIS) of ALT to evaluate the role of gene-environment interactions in fatty liver disease susceptibility and to identify new genetic determinant of NAFLD. We found a new locus interacting with body mass index (BMI), the strongest environmental risk factor for NAFLD, associated with liver fat and chronic liver disease, but not with ALT. In conclusion, these findings strongly support a causal relationship between liver fat accumulation and severe liver disease. Moreover, new genetic determinants of fatty liver identified by our analyses may be used for risk stratification of advanced liver disease and HCC, and exploited as potential drug targets.
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| 17. |
- Pennisi, Grazia, et al.
(författare)
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ANGPTL3 Downregulation Increases Intracellular Lipids by Reducing Energy Utilization.
- 2024
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636.
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Tidskriftsartikel (refereegranskat)abstract
- ANGPTL3 (angiopoietin-like protein 3) is a circulating protein with a key role in maintaining lipoprotein homeostasis. A monoclonal antibody against ANGPTL3 is an approved and well-tolerated treatment to reduce lipoproteins in familial hypercholesterolemia homozygotes. However, the reduction of hepatic ANGPTL3 synthesis using an antisense oligonucleotide unexpectedly resulted in a dose-dependent increase in liver lipid content and circulating transaminases, resulting in the termination of the clinical trial. Meanwhile, the use of silencing RNAs remains an area of active investigation. Our study sought to investigate whether intracellular downregulation of ANGPTL3 may lead to a primary increase in neutral lipids within the hepatocyte.We downregulated ANGPTL3 by silencing RNA in primary human hepatocytes 3-dimensional spheroids, HepG2/LX-2 3-dimensional spheroids, and in HepG2, Hep3B2, and Huh7 cultured in 2 dimensions.ANGPTL3 downregulation increased neutral lipids in all models investigated. Interestingly, ANGPTL3 induced lower intracellular deiodinase type 1 protein levels resulting in a reduction in beta-oxidation and causing an increase in triglycerides stored in lipid droplets.In conclusion, intracellular ANGPTL3 downregulation by silencing RNA led to an increase in triglycerides content due to a reduction in energy substrate utilization resembling a primary intracellular hepatocyte hypothyroidism.
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| 18. |
- Pipitone, Rosaria M., et al.
(författare)
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Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease
- 2023
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Ingår i: Liver International. - 1478-3223 .- 1478-3231. ; 43:8, s. 1761-71
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy. Methods: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele. Results: The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p =.01), NASH (OR 1.22, 95% CI 1.09-1.37; p <.001) and advanced fibrosis (OR 1.26, 95% CI 1.06-1.50; p =.007). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6. Conclusions: The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH.
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| 19. |
- Prill, S., et al.
(författare)
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The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- There is a high unmet need for developing treatments for nonalcoholic fatty liver disease (NAFLD), for which there are no approved drugs today. Here, we used a human in vitro disease model to understand mechanisms linked to genetic risk variants associated with NAFLD. The model is based on 3D spheroids from primary human hepatocytes from five different donors. Across these donors, we observed highly reproducible differences in the extent of steatosis induction, demonstrating that inter-donor variability is reflected in the in vitro model. Importantly, our data indicates that the genetic variant TM6SF2 E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion. Finally, differences in gene expression pathways involved in cholesterol, fatty acid and glucose metabolism between wild type and TM6SF2 E167K mutation carriers (N = 125) were confirmed in the in vitro model. Our data suggest that the 3D in vitro spheroids can be used to investigate the mechanisms underlying the association of human genetic variants associated with NAFLD. This model may also be suitable to discover new treatments against NAFLD.
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| 20. |
- Sasidharan, Kavitha, et al.
(författare)
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IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids.
- 2024
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Ingår i: Cell reports. Medicine. - 2666-3791. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate invitro that incubation with IL-32β protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD.
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| 21. |
- Tavaglione, Federica, et al.
(författare)
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Accuracy of controlled attenuation parameter for assessing liver steatosis in individuals with morbid obesity before bariatric surgery.
- 2022
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Ingår i: Liver international : official journal of the International Association for the Study of the Liver. - : Wiley. - 1478-3231. ; 42:2, s. 374-383
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Tidskriftsartikel (refereegranskat)abstract
- The ultrasound-based controlled attenuation parameter (CAP) is a non-invasive tool widely validated for assessing liver steatosis across different etiologies. However, few studies, with liver biopsy available, have investigated its performance in individuals with morbid obesity. Herein, we aimed to evaluate the diagnostic accuracy of CAP in participants with morbid obesity from the MAFALDA study before bariatric surgery.A total of 120 individuals with valid examinations within three months from bariatric surgery were included. Clinical, laboratory, FibroScan® (XL probe), and liver biopsy data were collected using standardized procedures. The overall accuracy of CAP for detecting liver steatosis was estimated by the area under the receiver-operating characteristics curve (AUROC). Optimal cut-offs were chosen at points with the highest Youden index.The AUROCs of CAP for detecting S≥S1, S≥S2, and S=S3 were 0.91 (95% CI 0.86-0.97), 0.83 (95% CI 0.76-0.90), and 0.86 (95% CI 0.79-0.94), respectively. The best CAP cut-offs for S≥S1, S≥S2, and S=S3 were 300dB/m (95% CI 275-316), 328dB/m (95% CI 296-345), and 344dB/m (95% CI 343-352), respectively. CAP values were independently influenced by steatosis grade (estimate 20.60, 95% CI 12.70-28.40, P=1.05×10-6 ). The AUROC of FibroScan-AST (FAST) score for detecting progressive non-alcoholic steatohepatitis was 0.76 (95% CI 0.66-0.86).In individuals with morbid obesity, CAP measured by XL probe is an accurate non-invasive tool for grading liver steatosis. Measurement of liver fat content by CAP may help identify those eligible for bariatric procedures and estimate the effect of bariatric surgery on hepatic steatosis.The ultrasound-based controlled attenuation parameter (CAP) by using the XL probe has an excellent performance for grading liver steatosis among individuals with morbid obesity. CAP may represent an accurate tool for the non-invasive assessment of liver steatosis among individuals with morbid obesity before and after bariatric surgery.
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| 22. |
- Tavaglione, Federica, et al.
(författare)
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Development and Validation of a Score for Fibrotic Non-Alcoholic Steatohepatitis.
- 2023
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Ingår i: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. - : Elsevier BV. - 1542-7714. ; 21:6, s. 1523-1532
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Tidskriftsartikel (refereegranskat)abstract
- Non-invasive assessment of histological features of non-alcoholic fatty liver disease (NAFLD) has been an intensive research area over the last decade. Herein, we aimed to develop a simple non-invasive score using routine laboratory tests to identify, among individuals at high risk for NAFLD, those with fibrotic non-alcoholic steatohepatitis (NASH) defined as NASH, NAFLD activity score (NAS) ≥4, and fibrosis stage ≥2.The derivation cohort included 264 morbidly obese individuals undergoing intraoperative liver biopsy in Rome, Italy. The best predictive model was developed and internally validated using a bootstrapping stepwise logistic regression analysis (2000 bootstrap samples). Performance was estimated by the area under the receiver operating characteristic curve (AUROC). External validation was assessed in three independent European cohorts (Finland, n=370; Italy n=947; England n=5,368) of individuals at high risk for NAFLD.The final predictive model, designated as Fibrotic NASH Index (FNI), combined aspartate aminotransferase (AST), high-density lipoprotein (HDL) cholesterol, and hemoglobin A1c (HbA1c). The performance of FNI for fibrotic NASH was satisfactory in both derivation and external validation cohorts (AUROCs 0.78 and 0.80-0.95, respectively). In the derivation cohort, rule-out and rule-in cut-offs were 0.10 for sensitivity ≥0.89 (negative predictive value [NPV] 0.93) and 0.33 for specificity ≥0.90 (positive predictive value [PPV] 0.57), respectively. In the external validation cohorts, sensitivity ranged from 0.87 to 1 (NPV 0.99-1) and specificity from 0.73 to 0.94 (PPV 0.12-0.49) for rule-out and rule-in cut-off, respectively.FNI is an accurate, simple, and affordable non-invasive score which can be used in primary healthcare to screen for fibrotic NASH individuals with dysmetabolism.
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| 23. |
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| 24. |
- Tavaglione, Federica, et al.
(författare)
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Inborn and acquired risk factors for severe liver disease in Europeans with type 2 diabetes from the UK Biobank.
- 2021
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Ingår i: JHEP reports : innovation in hepatology. - : Elsevier BV. - 2589-5559. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is a major driver of fatty liver disease and its long-term complications. The aim of this study was to investigate the individual contribution of inborn and acquired risk factors for severe liver disease in individuals with type 2 diabetes from the UK Biobank study.A total of 22,812 UK Biobank participants of European descent without clinical history of liver disease and liver cancer were prospectively followed for the development of severe liver disease, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation from the National Health Service records. The contribution of inborn and acquired risk factors to the risk of incident severe liver disease was assessed by Cox proportional hazards models.During a median follow-up of 8.9 years (IQR 8.1-9.6), there were 279 individuals with severe liver disease, including 255 with cirrhosis and/or decompensated liver disease, 47 with hepatocellular carcinoma, and 5 with liver transplantation; death from severe liver disease occurred in 83 individuals. Risk factors independently associated with increased risk of incident severe liver disease included abnormal aspartate aminotransferase (adjusted hazard ratio [aHR] 4.85, 95% CI 2.76-8.54), decrease in serum albumin (aHR 2.39, 95% CI 1.76-3.24) and platelet count (aHR 1.12, 95% CI 1.09-1.16), cardiovascular disease (aHR 1.86, 95% CI 1.23-2.79), microalbuminuria (aHR 1.55, 95% CI 1.04-2.30), PNPLA3 rs738409 (aHR 1.67, 95% CI 1.27-2.18) and TM6SF2 rs58542926 (aHR 1.63, 95% CI 1.12-2.39), while the net effect of male sex was protective (aHR 0.49, 95% CI 0.26-0.94).These findings may help in clinical care to identify individuals with type 2 diabetes at risk of severe liver disease, in turn leading to personalised risk prediction and prevention strategies.Type 2 diabetes is a key driver of severe liver disease, namely cirrhosis, hepatocellular carcinoma, and liver-related mortality. In Europeans with type 2 diabetes from the prospective UK Biobank study, abnormal liver function, cardiovascular disease, microalbuminuria, and genetic variants in PNPLA3 and TM6SF2 genes are the major independent risk factors for severe liver disease. These findings may contribute in clinical care to identify and closely monitor individuals with type 2 diabetes at risk of developing severe liver disease, requiring more intensive follow-up strategies.
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| 25. |
- Tavaglione, Federica, et al.
(författare)
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Machine learning reveals the contribution of lipoproteins to liver triglyceride content and inflammation.
- 2024
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Ingår i: The Journal of clinical endocrinology and metabolism. - 1945-7197.
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide and is strongly associated with metabolic comorbidities, including dyslipidemia.Herein, we aim to estimate the prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in Europeans with isolated hypercholesterolemia and isolated hypertriglyceridemia in the UK Biobank and to estimate the independent contribution of lipoproteins to liver triglyceride content.We selected 218,732 Europeans from the UK Biobank without chronic viral hepatitis and other causes of liver disease, of whom 14,937 with liver magnetic resonance imaging (MRI) data available. Next, to examine the relationships between traits in predicting liver triglyceride content, we compared the predictive performance of several machine learning methods and selected the best performing algorithms based on the minimum cross-validated mean squared error (MSE).There was an approximately 3-fold and 4-fold enrichment of MASLD and MASH in individuals with isolated hypertriglyceridemia (p=1.23E-41 and p=1.29E-10, respectively), whereas individuals with isolated hypercholesterolemia had a marginal higher rate of MASLD and no difference in MASH rate compared to control group (p=0.019 and p=0.97, respectively). Among machine learning methods, feed-forward neural network had the best cross-validation MSE on the validation set. Circulating triglycerides, after body mass index (BMI), were the second strongest independent predictor of liver proton density fat fraction (PDFF) with the largest absolute mean Shapley additive explanation (SHAP) value.Isolated hypertriglyceridemia is the second strongest, after obesity, independent predictor of MASLD/MASH. Individuals with hypertriglyceridemia, but not with hypercholesterolemia, should be screened for liver disease.
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