0000000000160703

AUTHOR

Serena Pelusi

showing 12 related works from this author

Rare <i>Atg7</i> Genetic Variants Predispose to Severe Fatty Liver Disease

2021

Background&Aims: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and has a strong heritable component. The aim of this study was to identify new genes involved in NAFLD pathogenesis. Methods: We examined rare variants captured by whole-exome sequencing in individuals with severe fibrosis or hepatocellular carcinoma due to NAFLD (severe NAFLD, n=301) after variant prioritization.  We replicated the results in the UK Biobank and the Liver biopsy cohort (n=2268). Results: We observed an enrichment of the p.P426L variant (rs143545741 C>T; OR=7.2, 2.3-17.3; p C; MAF=0.060 vs. 0.035; OR=1.7, 1.2-2.5; p=0.003). In the UK Biobank cohort, the p.V471A variant wa…

medicine.medical_specialtymedicine.diagnostic_testbusiness.industryFatty livermedicine.diseaseChronic liver diseaseGastroenterologyPathogenesisLiver diseaseBallooning degenerationLiver biopsyInternal medicineHepatocellular carcinomamedicineSteatosisbusinessSSRN Electronic Journal
researchProduct

Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nona…

2018

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 …

0301 basic medicinemedicine.medical_specialtySettore MED/12 - GASTROENTEROLOGIAPopulation03 medical and health sciencesLiver disease0302 clinical medicineLipid oxidationFibrosisInternal medicineNonalcoholic fatty liver diseasemedicineeducationNASH NAFLDeducation.field_of_studyHepatologymedicine.diagnostic_testbusiness.industryOriginal ArticlesHepatologymedicine.diseasen/a030104 developmental biologyEndocrinologyLiver biopsy030211 gastroenterology & hepatologyOriginal ArticleSteatosisbusiness
researchProduct

Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes.

2020

Background: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation. Methods: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes. Findings: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammatio…

Research paperTGFβ Transforming Growth Factor BetaIntracellular SpaceCRISPR Clustered Regularly Interspaced Short Palindromic RepeatshHEPS Human HepatocytesMice0302 clinical medicineLPIAT1DAG Diacylglyceroli.p. Intraperitonealmedia_commonFatty AcidsGeneral Medicine3. Good health030220 oncology & carcinogenesisHOMA-IR homeostasis Model Assessment of Insulin ResistanceMPO morpholinolcsh:Medicine (General)medicine.medical_specialtyPE Phosphatidyl-EthanolamineNashGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciencesTNFα tumor Necrosis Factor AlphaLDL Low Density LipoproteinsHyperinsulinismNAFLDSD Standard Dietmedia_common.cataloged_instanceHumansCPT1 Carnitine Palmitoyltransferase IPhosphatidylinositolGene SilencingEuropean unionVLDL Very Low Density Lipoproteinlcsh:RhHSC Human Hepatic Stellate Cellsmedicine.diseaseLipid MetabolismOA Oleic AcidCI Confidence IntervalMboat7 Membrane bound O-acyltransferase domain containing 7MCD methionine choline deficient diet030104 developmental biologyEndocrinologychemistryCDP Cytidine-DiphosphateFOXO1 Forkhead Box protein O1NAFLD nonalcoholic fatty liver diseaseSteatohepatitisBMI Body Mass IndexCL CardiolipinAcyltransferases0301 basic medicineAlcoholic liver diseaseCXCL10 C-X-C Motif Chemokine 10lcsh:Medicinechemistry.chemical_compoundNon-alcoholic Fatty Liver DiseaseIFG Impaired Fasting GlucoseAPOB Apolipoprotein BNonalcoholic fatty liver diseasePIP Phosphatidyl-Inositol-PhosphateSteatohepatitisqRT-PCR quantitative Real Time Polymerase Chain ReactionMice Knockoutlcsh:R5-920ORO Oil Red O StainingPI PhosphatidylinositolFatty liverTM6SF2 Transmembrane 6 Superfamily Member 2PhospholipidTAG TriglyceridesNASH Nonalcoholic SteatohepatitisLipogenesisLPA Lyso-Phosphatidic AcidPhosphatidylinositolSignal TransductionPS Phosphatidyl-SerinePA Palmitic AcidALD alcoholic liver diseasePC Phosphatidylcholinei.v. IntravenousFATP1 Fatty Acid Transport Protein 1Models BiologicalInternal medicinemedicineAnimalsNonalcoholic fatty liver diseasePPARα Peroxisome Proliferator-Activated Receptor alphaObesityG3P Glyceraldehyde-3-PhosphateSREBP1c Sterol Regulatory Element-Binding Protein 1HDL High Density Lipoproteinsbusiness.industryPI3K Phosphatidylinositol 3 KinaseMembrane ProteinsNHEJ Non-Homologues End JoiningPNPLA3 Patatin-like Phospholipase Domain-containing-3MTTP Microsomal Triglyceride Transfer ProteinLPIAT1 Lysophosphatidylinositol Acyltransferase 1TMC4 Transmembrane Channel-Like 4Disease Models AnimalGene Expression RegulationHepatocytesFOXA2 Forkhead Box A2mTOR mammalian target of RapamycinSteatosisInsulin ResistancebusinessPG Phosphatidyl-GlycerolFABP1 Fatty Acid-Binding Protein 1 FAS Fatty Acid SynthaseT2DM Type 2 Diabetes MellitusEBioMedicine
researchProduct

Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease

2017

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 frequ…

MaleCancer ResearchHepatocellular carcinomaSeverity of Illness IndexGermlineLoss of heterozygosityCohort StudiesLiver disease0302 clinical medicineNon-alcoholic Fatty Liver DiseaseNuclear Medicine and ImagingNonalcoholic fatty liver disease80 and overLeukocytesTelomeraseTelomere ShorteningOriginal ResearchCancer BiologyAged 80 and overHepatocellular carcinoma; Nonalcoholic fatty liver; Rare germline mutations; Telomerase reverse transcriptase; Telomere; Oncology; Radiology Nuclear Medicine and Imaging; Cancer ResearchtelomereLiver Neoplasmstelomerase reverse transcriptaseMiddle Aged3. Good healthPhenotypeOncology030220 oncology & carcinogenesisHepatocellular carcinoma030211 gastroenterology & hepatologyFemaleDisease SusceptibilityRadiologySequence AnalysisRare germline mutationCarcinoma HepatocellularMononuclearBiology03 medical and health sciencesGermline mutationHepatocellular carcinoma; Nonalcoholic fatty liver; Rare germline mutations; Telomerase reverse transcriptase; Telomere; Aged; Aged 80 and over; Alleles; Amino Acid Substitution; Carcinoma Hepatocellular; Cohort Studies; Computational Biology; Disease Susceptibility; Female; Genetic Association Studies; Humans; Leukocytes Mononuclear; Liver Neoplasms; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phenotype; Sequence Analysis DNA; Severity of Illness Index; Telomerase; Telomere; Telomere Shortening; Germ-Line Mutationmedicinenonalcoholic fatty liverHumansRadiology Nuclear Medicine and imagingTelomerase reverse transcriptaseAllelesGenetic Association StudiesGerm-Line MutationAgedrare germline mutationsCarcinomaComputational BiologyHepatocellularDNASequence Analysis DNAmedicine.diseasedigestive system diseasesTelomereAmino Acid SubstitutionCancer researchLeukocytes MononuclearCancer Medicine
researchProduct

Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores

2021

Background & Aims: 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. Methods: 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 …

0301 basic medicineOncologyLiver CirrhosisMaleMultifactorial InheritanceCirrhosis0302 clinical medicineRisk FactorsNon-alcoholic Fatty Liver DiseaseHepatic fatAdiposityeducation.field_of_studyFatty liverLiver NeoplasmsMiddle AgedPrognosisEuropeCirrhosisLiverCohort030211 gastroenterology & hepatologyBiomarker; Cirrhosis; Genetics; Hepatic fat; Non-alcoholic fatty liver diseaseFemaleLiver cancerCohort studymedicine.medical_specialtyCarcinoma HepatocellularSettore MED/12 - GASTROENTEROLOGIAPopulationRisk Assessment03 medical and health sciencesBiomarker Cirrhosis Genetics Hepatic fat Non-alcoholic fatty liver disease Cross-Sectional Studies Europe Female Genetic Predisposition to Disease Humans Liver Liver Cirrhosis Male Mediation Analysis Middle Aged Multifactorial Inheritance Predictive Value of Tests Prognosis Risk Assessment Risk Factors Adiposity Carcinoma Hepatocellular Non-alcoholic Fatty Liver DiseaseGeneticPredictive Value of TestsInternal medicinemedicineGenetic predispositionGeneticsHumansGenetic Predisposition to DiseaseeducationCirrhosiMediation AnalysisHepatologybusiness.industryCarcinomaCase-control studyHepatocellularBiomarkermedicine.diseasedigestive system diseases030104 developmental biologyCross-Sectional StudiesbusinessJournal of Hepatology
researchProduct

Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

2019

AbstractNonalcoholic 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 1000 G. 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 asso…

0301 basic medicineMaleCandidate geneApolipoprotein Blcsh:MedicineGastroenterologyLiver diseasechemistry.chemical_compound0302 clinical medicineNon-alcoholic Fatty Liver DiseaseRisk FactorsNonalcoholic fatty liver diseaseSequestosome-1 ProteinGenetic riskHCClcsh:ScienceMultidisciplinarybiologyLiver NeoplasmsMiddle Aged3. Good healthCholesterolHepatocellular carcinomaApolipoprotein B-100FemaleAged; Apolipoprotein B-100; Carcinoma Hepatocellular; Case-Control Studies; Cholesterol HDL; Female; Genetic Predisposition to Disease; Glial Cell Line-Derived Neurotrophic Factor Receptors; Humans; Liver Neoplasms; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Reproducibility of Results; Risk Factors; Sequestosome-1 Proteinmedicine.medical_specialtyCarcinoma HepatocellularGlial Cell Line-Derived Neurotrophic Factor ReceptorsHDLSettore BIO/18 - GENETICAdigestive systemArticle03 medical and health sciencesInternal medicinemedicineHumansGenetic Predisposition to DiseaseGeneAgedCholesterolbusiness.industrylcsh:RCarcinomaCholesterol HDLnutritional and metabolic diseasesReproducibility of ResultsHepatocellularmedicine.diseasedigestive system diseases030104 developmental biologychemistryNASH HCCCase-Control Studiesbiology.proteinlcsh:Qgeneticbusiness030217 neurology & neurosurgery
researchProduct

Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis

2019

In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis.We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also c…

AdultLiver CirrhosisMalemedicine.medical_specialtyBiopsydigestive systemGastroenterologyRisk Assessment03 medical and health sciences0302 clinical medicineFibrosisNon-alcoholic Fatty Liver DiseaseInternal medicineNonalcoholic fatty liver diseaseBiopsymedicinePrevalenceHumansrisk factorsRisk factorhistory; inflammatory response; progression; risk factorsHepatologymedicine.diagnostic_testbusiness.industryFatty liverGastroenterologynutritional and metabolic diseasesinflammatory responsemedicine.diseasedigestive system diseasesFatty LiverCross-Sectional StudiesItalyLiver030220 oncology & carcinogenesisLiver biopsyCohort030211 gastroenterology & hepatologyFemalehistoryprogressionSteatohepatitisbusiness
researchProduct

SARS-CoV-2 seroprevalence trends in healthy blood donors during the COVID-19 Milan outbreak

2020

Objectives: The Milan metropolitan area in Northern Italy was among the most severely hit by the SARS-CoV-2 outbreak. The epidemiological trends of mild COVID-19 are however still unknown. The aim of this study was to examine the seroprevalence of SARS-CoV-2 infection in healthy asymptomatic adults, the risk factors, and laboratory correlates. Design: We conducted a cross-sectional study during the outbreak. Presence of anti-SARS-CoV-2 IgM/IgG antibodies against the Nucleocapsid protein was assessed by a lateral flow immunoassay. Setting: Blood center at a leading academic hospital serving as COVID-19 referral center. Participants: We considered a random sample of blood donors since the sta…

0303 health sciencesmedicine.medical_specialtybiologymedicine.diagnostic_testbusiness.industryOutbreakLogistic regressionAsymptomatic3. Good health03 medical and health sciences0302 clinical medicineInternal medicineEpidemiologybiology.proteinmedicineSeroprevalence030212 general & internal medicineAntibodymedicine.symptomSeroconversionLipid profilebusiness030304 developmental biology
researchProduct

Transmembrane 6 Superfamily Member 2 Gene Variant Disentangles Nonalcoholic Steatohepatitis From Cardiovascular Disease

2015

Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed …

medicine.medical_specialtyHepatologymedicine.diagnostic_testbusiness.industryFatty liverOdds ratioHepatologymedicine.diseaseLower riskEndocrinologyInternal medicineLiver biopsyCohortmedicineSteatosisNASH TM6SF2businessTM6SF2
researchProduct

Renin-Angiotensin System Inhibitors, Type 2 Diabetes and Fibrosis Progression: An Observational Study in Patients with Nonalcoholic Fatty Liver Disea…

2016

Background The clinical determinants of fibrosis progression in nonalcoholic fatty liver disease (NAFLD) are still under definition. Aim To assess the clinical determinants of fibrosis progression rate (FPR) in NAFLD patients with baseline and follow-up histological evaluation, with a special focus on the impact of pharmacological therapy. Methods In an observational cohort of 118 Italian patients from tertiary referral centers, liver histology was evaluated according to Kleiner. Independent predictors of FPR were selected by a stepwise regression approach. Results Median follow-up was 36 months (IQR 24–77). Twenty-five patients (18%) showed some amelioration, 63 (53%) had stability, 30 (25…

0301 basic medicineLiver CirrhosisMalePeptide HormonesBiopsyTertiary Care Centerlcsh:MedicineBlood PressureAngiotensin-Converting Enzyme InhibitorsType 2 diabetesGastroenterologyVascular MedicineBiochemistryRenin-Angiotensin SystemTertiary Care Centers0302 clinical medicineFibrosisRetrospective StudieNon-alcoholic Fatty Liver DiseaseNonalcoholic fatty liver diseaseMedicine and Health SciencesEthnicitieslcsh:ScienceDiureticsMultidisciplinarymedicine.diagnostic_testMedicine (all)Liver DiseasesFatty liverAngiotensin Receptor AntagonistMiddle AgedPrognosisMetforminMetforminItalian PeopleItalyLiverHypertensionDisease Progression030211 gastroenterology & hepatologyFemaleAnatomymedicine.drugHumanResearch ArticleAdultmedicine.medical_specialtyHistologyPrognosiLiver CirrhosiAdrenergic beta-AntagonistsSurgical and Invasive Medical ProceduresGastroenterology and HepatologyFollow-Up Studie03 medical and health sciencesAngiotensin Receptor AntagonistsInternal medicineDiabetes mellitusBiopsymedicineDiureticHumansRetrospective StudiesBiochemistry Genetics and Molecular Biology (all)business.industrylcsh:RAdrenergic beta-Antagonistnutritional and metabolic diseasesBiology and Life SciencesRetrospective cohort studyAngiotensin-Converting Enzyme Inhibitormedicine.diseaseFibrosisHormonesFatty Liver030104 developmental biologyEndocrinologyAgricultural and Biological Sciences (all)Diabetes Mellitus Type 2People and Placeslcsh:QPopulation GroupingsHydroxymethylglutaryl-CoA Reductase InhibitorHydroxymethylglutaryl-CoA Reductase InhibitorsbusinessDevelopmental BiologyFollow-Up StudiesPLoS ONE
researchProduct

Rare ATG7 genetic variants predispose patients to severe fatty liver disease

2022

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 in-dividuals 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-rela…

InflammationLiver CirrhosisautophagyHepatologyBiopsyNAFLD NASH autophagy genetics liver fibrosisCarcinomaLiver NeoplasmsNASHHepatocellularAutophagy-Related Protein 7NAFLD; NASH; autophagy; genetics; liver fibrosis; Autophagy-Related Protein 7; Biopsy; Humans; Inflammation; Liver; Liver Cirrhosis; Carcinoma Hepatocellular; Liver Neoplasms; Non-alcoholic Fatty Liver DiseaseLiverNon-alcoholic Fatty Liver DiseaseNAFLDHumansgeneticsgeneticautophagy; genetics; liver fibrosis; NAFLD; NASHliver fibrosis
researchProduct

PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients

2019

Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLDrelated traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC (P < 0.05) and with hypercholesterolemia and liver disease …

0301 basic medicinenonalcoholic fatty liver diseasemedicine.medical_specialtyDyslipidemias; Genetics; Inflammation; Liver; Triglycerides; genes in lipid dysfunction; metabolic disease; non-alcoholic fatty liver diseaseHyperlipidemiasInflammationQD415-436030204 cardiovascular system & hematologyBiochemistryproprotein convertase subtilisin/kexin type 703 medical and health sciencesLiver disease0302 clinical medicineEndocrinologyGeneticInternal medicineNonalcoholic fatty liver diseasemedicineGeneticsHumansSubtilisinsAlleleTriglyceridesDyslipidemiasHypertriglyceridemiaInflammationgenes in lipid dysfunctionmedicine.diagnostic_testbusiness.industrynon-alcoholic fatty liver diseaseCell Biologymedicine.diseasemetabolic disease030104 developmental biologyEndocrinologyLiverLiver biopsyLipogenesisKexinmedicine.symptomPatient-Oriented and Epidemiological ResearchbusinessDyslipidemia
researchProduct