0000000000160707

AUTHOR

Rosellina Margherita Mancina

showing 13 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
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Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of 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
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PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD

2020

Background and Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low-density lipoprotein cholesterol (LDL-C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models. Methods: We considered 1874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA…

Malemedicine.medical_specialtyProprotein Convertase 9.GastroenterologyPCSK903 medical and health sciencesMice0302 clinical medicineFibrosisNon-alcoholic Fatty Liver DiseaseSettore BIO/13 - Biologia ApplicataInternal medicineNonalcoholic fatty liver diseaseMedicineSNPAnimalsHumansFIBROSISLoss functionSettore MED/12 - GastroenterologiaHepatologybusiness.industryAnimalPCSK9ConfoundingNASHCholesterol LDLProprotein convertasemedicine.diseaseLiver030220 oncology & carcinogenesisKexin030211 gastroenterology & hepatologyProprotein Convertase 9businessHuman
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A two gene-based risk score predicts alcoholic cirrhosis development in males with at-risk alcohol consumption

2019

Rosellina Margherita Mancina,1,* Flaminia Ferri,2,* Alessio Farcomeni,3 Antonio Molinaro,1 Angela Maffongelli,4 Monica Mischitelli,2 Edoardo Poli,2 Lucia Parlati,5 Maria Antonella Burza,6 Adriano De Santis,2 Fabio Attilia,2 Claudia Rotondo,2 Maria Margherita Rando,2 Maria Luisa Attilia,2 Mauro Ceccanti,2 Stefano Ginanni Corradini2 1Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, Wallenberg Laboratory, Göteborg, Sweden; 2Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy; 3Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; 4Department of Gener…

0301 basic medicineAlcoholic liver diseasemedicine.medical_specialtylcsh:QH426-470AlcoholGastroenterologyPredictive score03 medical and health scienceschemistry.chemical_compound0302 clinical medicineInternal medicinemedicineGeneticsAllelePNPLA3Genetics (clinical)Original Researchlcsh:R5-920Framingham Risk ScoreReceiver operating characteristicbusiness.industryIncidence (epidemiology)Alcoholic cirrhosis; CD14; PNPLA3; Predictive score; Genetics; Genetics (clinical)medicine.diseaselcsh:Genetics030104 developmental biologyAlcoholic cirrhosischemistryThe Application of Clinical Geneticsbusinesslcsh:Medicine (General)Settore SECS-S/01 - StatisticaCD14Body mass index030217 neurology & neurosurgeryTM6SF2The Application of Clinical Genetics
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Genetic variants in the MTHFR are not associated with fatty liver disease.

2020

The common missense sequence variants of methylenetetrahydrofolate reductase (MTHFR), rs1801131 (c.A1298C) and rs1801133 (c.C677T), favour 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 …

medicine.medical_specialtyHyperhomocysteinemiaGenotypeGastroenterologyPolymorphism Single Nucleotide03 medical and health sciences0302 clinical medicineNAFLDInternal medicinesteatosisMedicineMissense mutationHumansGenetic Predisposition to DiseaseFinlandMethylenetetrahydrofolate Reductase (NADPH2)Hepatologymedicine.diagnostic_testbiologybusiness.industryFatty liverNASHmedicine.diseaseFatty LiverCross-Sectional StudiesItaly030220 oncology & carcinogenesisLiver biopsyMethylenetetrahydrofolate reductaseCase-Control StudiesMTHFRDNA methylationCohortbiology.proteinfatty liver disease030211 gastroenterology & hepatologySteatosisfibrosibusinessLiver international : official journal of the International Association for the Study of the LiverREFERENCES
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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
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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

BACKGROUND & AIMS: 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. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine amino transferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants wit…

0301 basic medicineGenome-wide association studyLiver disease0302 clinical medicineENRICHMENT ANALYSISNon-alcoholic Fatty Liver DiseaseRisk FactorsNonalcoholic fatty liver diseaseExomeCONFERS SUSCEPTIBILITYGeneticsINSULIN-RESISTANCEmedicine.diagnostic_testFatty liverGastroenterologyAlanine Transaminase1-Acylglycerol-3-Phosphate O-Acyltransferase3. Good healthGENOMEEuropePhenotypeLiver biopsy030211 gastroenterology & hepatologyNonalcoholic Fatty Liver DiseaseMAFLDSingle-nucleotide polymorphismBiologyTransaminaseRisk Assessment03 medical and health sciencesApolipoproteins ENAFLDmedicineGenetic predispositionHumansGenetic Predisposition to DiseaseHEPATIC STEATOSISGenetic associationMAFLD Phenotype Reproducibility of Results Risk Assessment Risk Factors Transcriptome Genetic Variation Metabolic Associated Fatty Liver Disease Nonalcoholic Fatty Liver Disease Transaminase 1-Acylglycerol-3-Phosphate O-Acyltransferase Alanine Transaminase Apolipoproteins E Biomarkers Europe Exome Gene Expression Profiling Genetic Predisposition to Disease Genome-Wide Association Study Humans Non-alcoholic Fatty Liver DiseaseHepatologyMUTATIONSGene Expression ProfilingGenetic VariationReproducibility of Resultsmedicine.diseaseX-RECEPTORGENE030104 developmental biology3121 General medicine internal medicine and other clinical medicineMetabolic Associated Fatty Liver DiseaseRNA-SEQ DATATranscriptomePATHOGENICITYBiomarkersGenome-Wide Association StudyGastroenterology
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The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent

2016

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic…

Liver CirrhosisMale0301 basic medicineCirrhosisBiopsyProton Magnetic Resonance SpectroscopyPhosphatidylinositolsTriglycerideSeverity of Illness IndexGastroenterologyLiver disease0302 clinical medicineNon-alcoholic Fatty Liver DiseaseRisk FactorsNonalcoholic fatty liver diseaseMembrane Proteineducation.field_of_studyArachidonic Acidmedicine.diagnostic_testNASHGastroenterologyTexasEuropePhenotypeLiverLiver biopsyFemale030211 gastroenterology & hepatologyTexaCase-Control StudiePhosphatidylinositolHumanmedicine.medical_specialtyAcyltransferaseLiver CirrhosiEuropean Continental Ancestry GroupPopulationTM6SF2White PeopleArticle03 medical and health sciencesArachidonic Acid; NASH; PNPLA3; TM6SF2; Acetyltransferases; Acyltransferases; Biopsy; Case-Control Studies; Cross-Sectional Studies; Europe; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Liver; Liver Cirrhosis; Male; Membrane Proteins; Non-alcoholic Fatty Liver Disease; Phenotype; Phosphatidylinositols; Proton Magnetic Resonance Spectroscopy; Risk Factors; Severity of Illness Index; Texas; Triglycerides; Polymorphism GeneticGeneticAcetyltransferasesInternal medicineAcetyltransferasemedicineHumansGenetic Predisposition to DiseasePolymorphismeducationPNPLA3TriglyceridesCross-Sectional StudiePolymorphism GeneticHepatologybusiness.industryRisk FactorCase-control studyMembrane Proteinsmedicine.diseaseCross-Sectional Studies030104 developmental biologyEndocrinologyCase-Control StudiesSteatosisbusinessAcyltransferasesGenome-Wide Association StudyTM6SF2Gastroenterology
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The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage

2016

The patatin-like phosholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early-onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD nor in 100 healthy individuals with alanine aminotransferase22/20 IU/mL. …

AdultMale0301 basic medicinemedicine.medical_specialtyAdolescentPolymorphism Single Nucleotide03 medical and health sciences0302 clinical medicineNon-alcoholic Fatty Liver DiseaseLipid dropletInternal medicineNonalcoholic fatty liver diseasemedicineHumansGenetic Predisposition to DiseaseAlleleChildGeneticsHepatologybiologyMembrane ProteinsAlanine TransaminaseLipaseMiddle AgedHepatologyLipid Metabolismmedicine.diseasedigestive system diseases030104 developmental biologyEndocrinologyHaplotypesLiverAlanine transaminasePatatin-like phospholipaseadolescent; adult; alanine transaminase; case-control studies; child; female; genetic predisposition to disease; haplotypes; humans; lipase; lipid metabolism; liver; male; membrane proteins; middle aged; non-alcoholic fatty liver disease; polymorphism; single nucleotide; hepatologyCase-Control Studiesbiology.proteinFemale030211 gastroenterology & hepatologySteatosisSteatohepatitis
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Statin use and non-alcoholic steatohepatitis in at risk individuals.

2015

Background & Aims Excess hepatic free cholesterol contributes to the pathogenesis of non-alcoholic steatohepatitis, and statins reduce cholesterol synthesis. Aim of this study was to assess whether statin use is associated with histological liver damage related to steatohepatitis. Methods The relationship between statin use, genetic risk factors, and liver damage was assessed in a multi-center cohort of 1201 European individuals, who underwent liver biopsy for suspected non-alcoholic steatohepatitis. Results Statin use was recorded in 107 subjects, and was associated with protection from steatosis, NASH, and fibrosis stage F2-F4, in a dose-dependent manner (adjusted p <0.05 for all).…

AdultMaleRiskmedicine.medical_specialtyStatinmedicine.drug_classBiopsyGastroenterologyNon-alcoholic Fatty Liver DiseaseInternal medicinemedicineHumansSteatosiPNPLA3AgedHepatologymedicine.diagnostic_testbusiness.industryNASHStatinMembrane ProteinsLipaseHepatologyMiddle AgedImpaired fasting glucosemedicine.diseaseCholesterolEndocrinologyLogistic ModelsLiverLiver biopsyCohortFemaleSteatosisSteatohepatitisHydroxymethylglutaryl-CoA Reductase InhibitorsbusinessNon-alcoholic steatohepatitiTM6SF2Journal of hepatology
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<i>PCSK9</i> rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD

2020

Background and Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower LDL-C levels. In this study, we examined the impact of PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models. Methods: We considered 1,874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2…

medicine.medical_specialtyHuman liverbusiness.industryPCSK9Helsinki declarationFat accumulationInformed consentInternal medicineMedicinemedia_common.cataloged_instanceLiver damageEuropean unionbusinessPharmacogeneticsmedia_commonSSRN Electronic Journal
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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
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MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals

2017

AbstractNonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08–2.55; n = 765), particularly in those without advanced fibrosis (p < 0.001). The risk T allele was linked to 3’-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical fa…

0301 basic medicineLiver CirrhosisMaleAlcoholic liver diseasePathologyCirrhosisliver diseasesGastroenterology0302 clinical medicineSettore BIO/13 - Biologia ApplicataNon-alcoholic Fatty Liver DiseaseRisk FactorsNonalcoholic fatty liver diseasefatty liver-disease; cirrhosis; liver cancer; hepatitis C; hepatocellular carcinoma; liver diseases; fibrosis; carcinogenesis; fatty liver; allelesHCCProspective cohort studySettore MED/12 - GastroenterologiaMultidisciplinaryLiver NeoplasmsQRhepatocellular carcinomaSingle NucleotideMiddle Aged3. Good healthItalyfatty liver-diseaseHepatocellular carcinomaCohortMedicine030211 gastroenterology & hepatologyFemalecarcinogenesisAcyltransferases; Adult; Aged; Carcinoma Hepatocellular; Female; Gene Expression Regulation; Genotype; Humans; Italy; Liver Cirrhosis; Liver Neoplasms; Male; Membrane Proteins; Middle Aged; Non-alcoholic Fatty Liver Disease; Polymorphism Single Nucleotide; Risk Factors; Alleles; Genetic Association Studies; Genetic Predisposition to Disease; Genetic VariationAdultmedicine.medical_specialtyCarcinoma HepatocellularGenotypeSciencePolymorphism Single NucleotideArticleliver cancer03 medical and health sciencesInternal medicinemedicineHumansGenetic Predisposition to DiseaseAllelePolymorphismAllelesGenetic Association Studiesfatty liverAgedSettore MED/06 - ONCOLOGIA MEDICAbusiness.industrycirrhosisfibrosisCarcinomaGenetic VariationMembrane ProteinsHepatocellularmedicine.diseasedigestive system diseases030104 developmental biologyGene Expression Regulationhepatitis CbusinessAcyltransferasesTM6SF2Scientific Reports
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